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Biomedical subjects

A Gruber

Publications and source records attributed to A Gruber.

At least 91 records · Page 5Linked to original sources
PubMed1999

The influence of subinhibitory concentrations of conventional and experimental antifungal drugs on the expression of the iC3b binding protein in Candida albicans strains during filamentation.

The influence of six antifungal agents on the expression of the fungal iC3b binding protein was studied in germ-tubes and the mycelial form of several Candida albicans strains. All antifungal agents inhibited not only the yeast-mycelial transformation, but also the formation of rosettes consisting of complement-coated sheep erythrocytes (EAiC3b) bound to the mycelial form of C. albicans. Immunofluorescence as well as ELISA, employing the monoclonal antibody OKM-1 which recognizes the alpha chain of human CR3 and which cross-reacts with the fungal iC3b binding protein, revealed that subinhibitory concentrations of 0.1 mg l(-1) (which did not affect the growth of either germ-tubes or the mycelial form of C. albicans) inhibited the expression of the iC3b binding protein, while lower concentrations (0.01 mg l(-1)) allowed a comparable and sometimes even slightly higher expression of this protein, in comparison with the untreated control. However, treatment with antifungal agents apparently did not lead to a major cleavage of the protein. The dependence of the amount of the iC3b binding protein expressed on the concentration of added antifungal drugs and on the morphological forms of individual C. albicans isolates suggests a drug dependent influence on the expression of this protein and a possible association with the changing virulence of C. albicans strains during antifungal therapy.

Amphotericin B↗
PubMed1999

Brain-specific protein C activation during carotid artery occlusion in humans.

BACKGROUND AND PURPOSE: Activation of plasma protein C (PC) zymogen by thrombin-thrombomodulin at the endothelial surface is an important endogenous antithrombotic mechanism. It is unknown whether activated protein C (APC) is generated in vivo in the cerebrovasculature, because there is only limited thrombomodulin expression in human brain vascular endothelium. Therefore, we tested the hypothesis that carotid occlusion produces brain-specific PC activation. METHODS: Blood samples were simultaneously collected from the ipsilateral internal jugular vein and radial artery before and during carotid cross-clamping and on "de-occlusion" in 8 awake patients undergoing routine carotid endarterectomy. Plasma PC zymogen and circulating APC levels were measured using enzyme immunocapture assay and expressed as percent of pooled plasma controls. RESULTS: Internal jugular vein APC levels increased 28% exclusively during carotid occlusion and then decreased 32% with de-occlusion (F=8.1, P<0.005). PC zymogen increased only 5.9% with occlusion (F=6.3, P<0.02), consistent with hemoconcentration. There were no changes in radial artery PC or APC levels. CONCLUSIONS: These findings demonstrate brain-specific protein C activation in humans during carotid occlusion and suggest a protective role for endogenous APC generation during cerebrovascular occlusion.

Aged↗
PubMed1999

Variant arteriovenous fistula of the superior sagittal sinus--case report.

A 57-year-old male presented with a rare variant of dural arteriovenous fistula, located in the wall of an unobstructed superior sagittal sinus. Drainage occurred through a cortical vein no longer connected to its parent sinus, which filled up a cluster of transmedullary running veins, one of which was the presumed site of hemorrhage. Arterial blood was supplied via the external carotid artery branches. This type of fistula seriously increases the risk of hemorrhage in the patient and therefore requires complete obliteration. Attempts to embolize the fistula failed. The draining vein was isolated and coagulated resulting in permanent occlusion of the fistula. The fistula probably developed through a process of thrombophlebitis and revascularization via arterioles of the vein rather than previous occlusion of the sinus.

Arteriovenous Fistula↗
PubMed1999

Intraclonal heterogeneity in the in vitro daunorubicin-induced apoptosis in acute myeloid leukemia.

Leukemic cells from ten patients with acute myeloid leukemia (AML) were sorted on the basis of in vitro daunorubicin (DNR) uptake. The obtained subpopulations with high and low DNR accumulation were compared with regard to induction of apoptosis, expression of bcl-2 and p53. Heterogeneous induction of apoptosis, confined to subpopulations with high DNR uptake, was observed. The size of the DNR-induced apoptotic fraction (4% to 16%) within a given AML blast population was determined by intracellular drug accumulation and was not related to the level of bcl-2 expression. All tested leukemic samples displayed expression of p53 in a growth promoter orientation, i.e. PAb1620-/PAb240+. In two samples, however, subpopulations expressing a growth suppressor orientation of p53, i.e. PAb 1620+/PAb240-, were also present. These subpopulations were confined to high-DNR-uptake fractions and associated with the induction of apoptosis. We conclude that intraclonal heterogeneity in the intracellular drug accumulation and subsequently in DNR-induced apoptosis might allow the selection of inherently drug-resistant AML clones thus contributing to relapse of leukemia.

Acute Disease↗
PubMed1999

Treatment of basilar artery bifurcation aneurysms by using Guglielmi detachable coils: a 6-year experience.

OBJECT: The authors retrospectively analyzed the results of their 6-year experience in the treatment of basilar artery (BA) bifurcation aneurysms by using Guglielmi detachable coils (GDCs). METHODS: This analysis involved 45 BA tip aneurysms in 16 men and 29 women who ranged in age from 23 to 78 years (mean 50 years). Seventy-five percent of the aneurysms had ruptured and 25% remained unruptured. Of the group whose aneurysms hemorrhaged, 14 patients were Hunt and Hess Grade I or II and 20 were Hunt and Hess Grades III to V; 32 patients were treated within 2 weeks of their subarachnoid hemorrhage (SAH). Initially, treatment with GDCs was limited to poor-grade high-risk patients who refused surgery or patients in whom surgery proved unsuccessful. Later in the study, good-grade patients with narrow-necked aneurysms were also treated using GDCs. The length of clinical follow up ranged from 1 to 72 months (average 27.4 months) in the 37 surviving patients. In 33 of the 45 aneurysms treated with coil placement, good to excellent results were achieved. There were 12 poor results (27%) including one in a patient from the non-SAH group who suffered a thrombotic complication due to an underlying vasculitis. Eight deaths were recorded in this group of 45 patients. One of these deaths was caused by a complication related to anesthesia, one by unknown causes, and six resulted from complications of the disease. One patient rebled on the 2nd day after the endovascular procedure. The mortality and permanent morbidity rates directly related to the intervention were 2.2% and 4.4%, respectively. Angiographic studies obtained immediately postintervention demonstrated 99 to 100% occlusion in 30 (67%) of the aneurysms; nine (20%) were more than 90% occluded; and six (13%) were less than 90% occluded by the GDCs. Follow-up angiograms were obtained in 31 patients between 2 and 72 months after coil placement. Nineteen (61%) of the follow-up angiograms revealed stable results (that is, no change from initial treatment). Twelve of the 31 showed coil compaction, but only eight of these lesions could accept additional coils. In large aneurysms recanalization was seen in 57%, and some of the larger lesions required as many as four embolizations (mean 1.7) to achieve optimal occlusion. When small-necked aneurysms were analyzed as a subset, a stable angiographic result was seen in 92%. CONCLUSIONS: Use of GDCs led to excellent clinical and angiographic results in the majority of patients with BA tip aneurysms included in this limited follow-up study. Rebleeding was encountered in one of the 34 previously ruptured BA aneurysms treated with GDCs, and no hemorrhages have been documented in the 11 unruptured aneurysms treated with GDCs in this series. Long-term follow-up studies are necessary before it is possible to compare adequately the treatment of aneurysms with coil placement to the gold standard of aneurysm clipping.

Adult↗
PubMed1999

Gross and microscopic histopathological findings in aneurysms of the human brain treated with Guglielmi detachable coils.

OBJECT: The histopathological characteristics of aneurysms obtained at autopsy or surgery 3 days to 54 months after being treated with Guglielmi detachable coils (GDCs) were assessed. METHODS: Seventeen aneurysms were obtained at autopsy and one was removed at surgery. Fourteen were examined histologically with the coils in situ. Naked coils embedded in an unorganized thrombus were found in those aneurysms that had been treated with coils within 1 week earlier. An incomplete replacement of the intraluminal blood clot by fibrous tissue and a partial membranous covering at the aneurysm orifice were observed in those aneurysms that had been treated with coils between 2 and 3 weeks prior to examination. One small aneurysm treated 6 weeks before harvesting showed formation of an endothelium-lined layer of connective tissue at the orifice. Collagen-rich vascularized tissue surrounding the coils was found in an aneurysm removed at surgery 54 months after coil implantation. Interestingly, six (50%) of 12 aneurysms (two small, three large, and one giant) that had been deemed 100% occluded on initial angiography showed tiny open spaces between the coils at the neck on gross examination. CONCLUSIONS: Endothelialization of the aneurysm orifice following placement of GDCs can occur; however, it appears to be the exception rather than the rule. In large aneurysms the process of intraaneurysm clot organization seems to be delayed and incomplete; tiny open spaces between the coils and an incomplete membranous covering in the region of the neck are frequently encountered. Further longitudinal studies are required to establish the spectrum of healing profiles that may direct our efforts in modifying the GDC system to produce a more stable long-term result.

Adult↗
PubMed1999

Etoposide-induced DNA strand breaks in relation to p-glycoprotein and topoisomerase II protein expression in leukaemic cells from patients with AML and CLL.

Elevated expression of the membrane transporter p-glycoprotein (pgp) and impaired expression of the nuclear enzyme topoisomerase II (topo II) are well-known mechanisms for in vitro acquired drug resistance. The clinical relevance of topo II remains unclear, whereas a relationship between pgp levels and treatment results has been shown in acute myelogenous leukaemia (AML). We have investigated the relationships between the levels of topo II and pgp, and in vitro sensitivity to etoposide in mononuclear blood cells from 24 patients with AML, 16 with chronic lymphocytic leukaemia (CLL) and five healthy blood donors. Following incubation with etoposide, AML cells showed more DNA damage, determined by a DNA unwinding technique, than CLL cells (P = 0.001), whereas there was no difference in cellular etoposide accumulation. Pgp and topo IIbeta levels, determined by Western blot, showed a pronounced variation between patients, but no correlation with induced DNA damage, whereas topo IIalpha protein was undetectable. In the AML group, topo IIbeta expression correlated with pgp expression (rho = 0.7, P = 0.001, n = 24). The topo IIbeta expression was 147.4(+/-74.6)% in the pgp+ AML cells (n = 10), compared to 33.4(+/-27.8)% in pgp- AML cells (n = 14) (P = 0.0001). Our results show a previously unknown coexpression of topo IIbeta and pgp in AML, thereby suggesting that topo IIbeta is a potentially interesting resistance factor in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells.

Lipoprotein(a) [Lp(a)] consists of LDL and the glycoprotein apolipoprotein(a) [apo(a)], which are covalently linked via a single disulfide bridge. The formation of Lp(a) occurs extracellularly, but an intracellular assembly in human liver cells has also been claimed. The human apo(a) gene locus is highly polymorphic due to a variable number of tandemly arranged kringle IV repeats. The size of apo(a) isoforms correlates inversely with Lp(a) plasma concentrations, which is believed to reflect different synthesis rates. To examine this association at the cellular level, we analyzed the subcellular localization and fate of apo(a) in stably transfected HepG2 cells. Our results demonstrate that apo(a) is synthesized as a precursor with a lower molecular mass which is processed into the mature, secreted form. The retention times of the precursor in the ER positively correlated with the sizes of apo(a) isoforms. The mature form was observed intracellularly at low levels and only in the Golgi apparatus. No apo(a) was found to be associated with the plasma membrane. Under temperature-blocking conditions, we did not detect any apo(a)/apoB-100 complexes within cells. This finding was confirmed in HepG2 cells transiently expressing KDEL-tagged apo(a). The precursor and the mature forms of apo(a) were found in the ER and Golgi fractions, respectively, also in human liver tissue. From our data, we conclude that in HepG2 cells the apo(a) precursor, dependent on the apo(a) isoform, is retained in the ER for a prolonged period of time, possibly due to an extensive maturation process of this large protein. The assembly of Lp(a) takes place exclusively extracellularly following the separate secretion of apo(a) and apoB.

Apolipoproteins A↗
PubMed1998

Angiogenesis and brain oedema in intracranial meningiomas: influence of vascular endothelial growth factor.

The correlation between angiographic neovascularization, peritumoural brain oedema (PTBOe) and the expression of vascular endothelial growth factor (VEGF), was analysed in 30 patients with intracranial meningiomas. Pre-operative angiograms were examined for the existence of either an exclusively dural tumour blush or an additionally pial tumour supply from cerebral arteries. Furthermore the presence of macroscopic tumour-neovascularization and dysplastic changes of tumour-draining cerebral veins was evaluated. VEGF expression was investigated on histological tissue samples, using immunohistochemical techniques. VEGF immunohistochemistry and neuroradiological evaluations were performed in double blind fashion. Tumour volume and the amount of oedema were calculated by computerized tomography (CT) or magnetic resonance imaging (MRI). The oedema-tumour volume ratio was defined as oedema index (OeI). Compared to VEGF-negative meningiomas, tumours with striking VEGF staining revealed a significant higher mean oedema index (OeI = 4.2 vs. OeI = 1.5; p < 0.018), and a higher oedema incidence (91.7% vs. 44.4%; p < 0.046). Equally, meningiomas with additionally tumour supply from cerebral arteries were associated with a significant higher mean OeI (OeI = 4.1 vs. OeI = 1.2; p < 0.01) and oedema incidence (94.7% vs. 20.0%; p < 0.0023) than meningiomas with exclusively tumour supply from dural arteries. All meningiomas with striking VEGF-expression were associated with vascular tumour supply from cerebral arteries, but VEGF-negative tumours only in 50% (p < 0.029). These data suggest a link between VEGF-expression, arterial tumour supply and peritumoural brain oedema. The development of tumour supply from cerebral arteries may be important for formation of meningioma-related oedema. Therefore, VEGF may represent a potent mediator in the evolution of this type of vascularization in meningiomas.

Adult↗
PubMed1998

Projection noise in the optically detected magnetic resonance signal of a single electron spin.

The spin quantum noise owing to a single molecular triplet electron spin jumping from one eigenstate to another has been detected. As a result of the superposition of two spin eigenstates in the triplet level of the molecule by a microwave pi/2-pulse an increase in the noise of the fluorescence intensity of a single molecule is detected. This increase in noise is attributed to the decay of coherence between the two spin eigenstates.

Electrons↗
PubMed1998

Multidrug resistance phenotype in leukaemic cells from patients with acute myelocytic leukaemia can be detected with 99Tc(m)-MIBI.

The aim of the study was to investigate whether 99Tc(m)-MIBI (Cardiolite), recently shown to be a substrate for P-glycoprotein, has the potential to be used as a marker for mdr1 gene expression and whether cyclosporin A (CyA) can modify its accumulation in vivo. Leukaemic cells from ten patients with acute myelocytic leukaemia (AML) were used, five with undetectable mdr1 gene expression and five with mdr1 mRNA levels ranging from 1.0 to 3.8 mdr1 mRNA transcripts per cell. Cells were incubated with 99Tc(m)-MIBI, or with daunorubicin (Dnr), with and without 3 microM CyA. The median 99Tc(m)-MIBI accumulation (% of added radioactivity) in mdr1-negative cells was 0.89% and in the mdr1-positive cells 0.34%, P = 0.01. In mdr1-negative cells, the median increase in 99Tc(m)-MIBI accumulation with CyA was 30% compared with the mdr1-positive cells with a median increase of 242%, P = 0.009. CyA had no significant effect on Dnr accumulation in four of the mdr1-negative samples. The median increase of Dnr accumulation in the mdr1-positive cells was 40%. The results show that 99Tc(m)-MIBI with a high sensitivity can detect rather low levels of mdr1 gene expression in clinical samples. Consequently, 99T(c)m-MIBI scintigraphy has the potential to be used for monitoring the effect of resistance modifiers on the accumulation and retention of cytostatic drugs in human tumours in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Telomerase activity and the expression of telomerase components in acute myelogenous leukaemia.

In 95 leukaemic cell samples from 66 patients with acute myelogenous leukaemia (AML) (47 de novo and 19 secondary AML) telomerase activity was determined and the expression of the telomerase components: telomerase reverse transcriptase (hTERT), telomerase RNA template (hTR) and telomerase-associated protein (TP1) evaluated by RT-PCR. Compared to peripheral blood mononuclear cells (PBMC) from normal adult 87% (82/95) of patient samples exhibited elevated telomerase activity hTERT, but not hTR and TP1 expression strongly correlated with the levels of telomerase activity (r=0.47, P<0.0001). The levels of telomerase activity were significantly higher at time of relapse or progression than at time of diagnosis (P=0.003), and correlated to CD34 expression and chromosomal abnormalities of leukaemic cells (P=0.01 and P=0.001 respectively). The rate and duration of complete remission (CR) did not correlate with the levels of telomerase activity at diagnosis. Among eight patients in first relapse, however, two of three with low levels of telomerase activity re-entered CR. whereas none of five patients with high telomerase activity achieved a second CR. Taken together, telomerase activation/up-regulation in AML is a disease progression-associated event. Undifferentiated status and chromosomal aberration also lead to the up-regulation of telomerase activity in AML.

Adult↗
PubMed1998

Experimental bifurcation aneurysm: a model for in vivo evaluation of endovascular techniques.

An experimental aneurysm model for in vivo testing of endovascular techniques is described. The aneurysm is produced surgically in the neck of the rabbit by partial anastomosis of the left to the right common carotid artery, thus creating an arterial bifurcation. Subsequently, a venous pouch is sutured into the artificial bifurcation. The size of the arteries, coagulation profile and hemodynamic features in this aneurysm model closely mimic human conditions. Surgical technique and our preliminary experience with this model are discussed.

Animals↗
PubMed1998

Human immunodeficiency virus type 1 gp160 and gp41 binding to Candida albicans selectively enhances candidal virulence in vitro.

Previously, it has been shown that human immunodeficiency virus (HIV)-1 envelope proteins gp160 and gp41 bind to Candida albicans. Whether this interaction affects candidal virulence in vitro was investigated. HIV-1 gp160 or gp120 treatment of C. albicans significantly altered neither growth nor phospholipase activity of the fungus. However, treatment of C. albicans with gp160, but not with gp120, led to an elevation of free and cell-bound aspartate proteinase. In addition, culture supernatants obtained from C. albicans treated with gp160 or gp41, but not with gp120, showed a strong increase in proteinase activity. Finally, C. albicans viable yeast cells treated with gp160 or gp41 and serum were phagocytosed by polymorphonuclear leukocytes to a lesser extent than was C. albicans treated with gp120 and serum or serum alone. These findings suggest that the interaction between HIV-1 gp160 and C. albicans may promote the virulence of C. albicans in HIV-1-positive patients.

Antigens, Fungal↗
PubMed1998

Evaluation of cerebral vasospasm after early surgical and endovascular treatment of ruptured intracranial aneurysms.

OBJECTIVE: To document the influence of the treatment modality (early surgery versus early endovascular treatment) on measures of cerebral vasospasm in a nonrandomized series of 156 patients treated within 72 hours of aneurysmal subarachnoid hemorrhage. METHODS: The following parameters were prospectively collected in a computerized data base and retrospectively analyzed for association with vasospasm-related ischemic infarctions: 1) Hunt and Hess (H&H) grade, 2) Fisher grade, 3) highest mean cerebral blood flow velocity (CBFVMAX) and maximum percent change in mean CBFV (%deltaCBFV) as recorded by transcranial Doppler ultrasound, 4) incidence of repeat subarachnoid hemorrhage, 5) incidence of delayed ischemic neurological deficits, 6) incidence of delayed ischemic infarctions, and 7) Glasgow Outcome Scale score. RESULTS: Forty-one patients (26.3%) suffered ischemic infarctions. The ischemic infarction rate was correlated with higher H&H grade (P = 0.002), higher Fisher grade (P = 0.05), higher CBFVMAX (P < 0.001) and %deltaCBFV (P = 0.01), occurrence of repeat subarachnoid hemorrhage, occurrence of delayed ischemic neurological deficits, and endovascular treatment (P = 0.02). CONCLUSION: The infarction rate was higher with endovascular treatment versus surgery (37.7 versus 21.6%), as a result of a skewed Fisher Grade 4 infarction pattern in the endovascular treatment group versus the surgery treatment group (66.7 versus 24.5%). We suspect that unremoved subarachnoid/intracerebral clots contributed to the higher infarction rate with endovascular treatment. When patients with Fisher Grade 4 and H&H Grade V were excluded from analysis, the difference in infarct incidence between the treatment groups no longer reached statistical significance (Fisher Grades 1-3, P = 0.49; H&H Grades I-IV, P = 0.96).

Adult↗
PubMed1998

Extracellular ATP causes apoptosis and necrosis of cultured mesangial cells via P2Z/P2X7 receptors.

Mesangial cells undergo cell death both by apoptosis and necrosis during glomerular disease. Since nucleotides are released from injured and destroyed cells in the glomerulus, we examined whether extracellular ATP and its receptors may regulate cell death of cultured mesangial cells. Addition of extracellular ATP (300 microM to 5 mM) to cultured rat mesangial cells for 90 min caused a 5. 8-fold increase in DNA fragmentation (terminal deoxynucleotidyl transferase assay) and a 4.2-fold increase in protein levels of the tumor suppressor p53, which is thought to regulate apoptosis. Apoptotic DNA fragmentation was confirmed by the diphenylamine assay and by staining with the DNA-specific fluorochrome Hoechst 33258. The necrotic markers, release of lactate dehydrogenase and uptake of trypan blue, were not positive before 3 h of ATP addition. The effects of ATP on DNA fragmentation and p53 expression were reproduced by the purinergic P2Z/P2X7 receptor agonist, 3'-O-(4-benzoylbenzoyl)-ATP, and inhibited by the P2Z/P2X7 receptor blocker, oxidized ATP. Transcripts encoding the P2Z/P2X7 receptor were expressed by cultured mesangial cells as determined by Northern blot analysis. P2Z/P2X7 receptor-associated pore formation in the plasma membrane was demonstrated by the Lucifer yellow assay. We conclude that activation of P2Z/P2X7 receptors by extracellular ATP causes apoptosis and necrosis of cultured mesangial cells. Activation of purinergic P2Z/P2X7 receptors may play a role in causing death of mesangial cells during glomerular disease.

Adenosine Triphosphate↗
PubMed1998

Pulmonary function and radiographic abnormalities related to neurological outcome after aneurysmal subarachnoid hemorrhage.

OBJECT: This observational study is based on a consecutive series of 207 patients with aneurysmal subarachnoid hemorrhage who were treated within 7 days of their most recent bleed. The purpose of the study was to evaluate the effect of respiratory failure on neurological outcome. METHODS: Pulmonary function was assessed by determination of parameters describing pulmonary oxygen transport and exchange, by using composite scores for quantification of lung injury (lung injury score [LIS]) and mechanical ventilator settings (PIF score). Pulmonary function was related to the Hunt and Hess (H & H) grade assigned to the patient at hospital admission (p < 0.001). The pattern and time course of lung injury differed significantly between patients with H & H Grade I or II, Grade III, and Grade IV or V. Hunt and Hess grade, Fisher computerized tomography grade, intracranial pressure, cerebral perfusion pressure, LIS, ratio of PaO2 to the fraction of inspired oxygen (FiO2), and the ratio of the alveolar-minus-arterial oxygen tension difference (AaDO2) to FiO2 were related to neurological outcome (p < 0.001). The LIS on the day of maximum lung injury remained an independent predictor of outcome (p = 0.01) in a stepwise logistic regression analysis. The probability of poor neurological outcome significantly increased with both decreasing cerebral perfusion pressure and increasing severity of lung injury. CONCLUSIONS: The overall mortality rate was 22.2% (46 of 207 patients). Subarachnoid hemorrhage and its neurological sequelae accounted for the principal mortality in this series. Medical (nonneurological and nontreatment-related) complications accounted for 37% of all deaths. Systemic inflammatory response syndrome with associated multiple organ dysfunction syndrome was the leading cause of death from medical complications. The authors conclude that respiratory failure is related to neurological outcome, although it is not commonly the primary cause of death from medical complications.

Adult↗