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Biomedical subjects

S Engel

Publications and source records attributed to S Engel.

At least 19 recordsLinked to original sources
PubMed2004

The Gene Ontology (GO) database and informatics resource.

The Gene Ontology (GO) project (http://www. geneontology.org/) provides structured, controlled vocabularies and classifications that cover several domains of molecular and cellular biology and are freely available for community use in the annotation of genes, gene products and sequences. Many model organism databases and genome annotation groups use the GO and contribute their annotation sets to the GO resource. The GO database integrates the vocabularies and contributed annotations and provides full access to this information in several formats. Members of the GO Consortium continually work collectively, involving outside experts as needed, to expand and update the GO vocabularies. The GO Web resource also provides access to extensive documentation about the GO project and links to applications that use GO data for functional analyses.

Animals↗
PubMed2003

21Na(p,gamma)22Mg reaction and oxygen-neon novae.

The 21Na(p,gamma)22Mg reaction is expected to play an important role in the nucleosynthesis of 22Na in oxygen-neon novae. The decay of 22Na leads to the emission of a characteristic 1.275 MeV gamma-ray line. This report provides the first direct measurement of the rate of this reaction using a radioactive 21Na beam, and discusses its astrophysical implications. The energy of the important state was measured to be E(c.m.)=205.7+/-0.5 keV with a resonance strength omegagamma=1.03+/-0.16(stat)+/-0.14(sys) meV.

Journal Article↗
PubMed2002

Do siblings of myocardial infarction patients have a specific management of hypertension?

The aim of this study was to determine whether the management of hypertension differs between siblings of myocardial infarction patients and the general population. Siblings aged 35 to 74 years, unaffected by myocardial infarction, were drawn from the Augsburg Family Heart Study, conducted in 1996-1997 in southern Germany (n = 524). The reference group consisted of participants of the third MONICA population-based survey conducted in 1994-1995 in the same area, who were aged 35 to 74 years and also unaffected by myocardial infarction (n = 3802). Prevalence, awareness, treatment and control of hypertension (defined by blood pressure > or = 140/90 mm Hg or use of antihypertensive medication) were compared between the two groups. The result was that the prevalence of hypertension was higher in the siblings (men: age-adjusted OR = 1.31, 95% CI: 0.99-1.75; women: age-adjusted OR = 1.83, 95% CI: 1.39-2.41). Male hypertensive siblings were more often aware and treated for hypertension than male hypertensives of the reference group whereas the level of awareness and treatment was comparable between female hypertensives of the two groups. In both genders, no difference in the degree of control was shown between hypertensives of the two groups. In conclusion the siblings and their physicians should pay more attention to the family history of myocardial infarction in order to improve the management of hypertension in this high risk group.

Adult↗
PubMed2001

Genetic perspectives on the serotonin transporter.

The serotonin transporter (5-HTT) is most well known as the site of action of the serotonin reuptake inhibitors, which were initially developed as antidepressants, but now are the most widely used agents in the treatment of many additional neuropsychiatric and related disorders. The discovery that the gene that expresses the 5-HTT possesses a functional promoter-region polymorphism, which is associated with temperament and personality traits such as anxiety and negative emotionality as well as some behaviors, led to many studies examining this polymorphism in individuals with different neuropsychiatric disorders. The subsequent development of mice with a targeted disruption of the 5-HTT in our laboratory has provided an experimental model to examine the many consequences of diminished (in +/-, heterozygote mice) or absent (in -/-, homozygote knockout mice) function of the 5-HTT. The 5-HTT-deficient mice were also crossed with other knockout mice, allowing the study of multiple neurobiologic dysfunctions. As multiple genes are probably involved in the expression of complex behaviors such as anxiety, as well as neuropsychiatric disorders, these more genetically complex mice may more closely model disorders with complex etiologies. Thus, the combination of these comparative human and mouse studies may extend the opportunities to examine genetic alterations from a novel "bottom-up" approach [gene knockout or partial gene knockout in a combinational gene x gene x (yet unknown) gene approach], which is complementary to the traditional "top-down" genetic approach based upon studies of individuals with diagnosed neuropsychiatric disorders and their family members.

Animals↗
PubMed2001

Negative functional effects of cGMP mediated by cGMP protein kinase are reduced in T4 cardiac myocytes.

We tested the hypothesis that in isolated rabbit cardiac myocytes, the negative functional effects of cyclic GMP are partly mediated by cyclic GMP-dependent protein kinase activity, and that these effects are altered in thyroxine (T4, 0.5 mg/kg/day for 16 days)-induced hypertrophic myocytes. Using isolated ventricular myocytes from control (N=8) and T4 (N=8) hypertrophic hearts, data for percent cell shortening (%) and maximum rate of contraction (microm/s) were collected using a video edge detector at baseline, after the addition of 10(-6) M 8-bromo-cyclic GMP (8-Br-cGMP), 10(-5) M 8-Br-cGMP, and 10(-6) M KT5823 (10-methoxy-10-methoxycarbonyl-9, 10, 11, 12-tetrahydro-9, 12-epoxy-(1H)-diinidolo [1, 2, 3, f-g: 3', 2', 1'-k-j]-pyrrolidino-[3,4-i] [1,6]-benzodiazocin-2-methyl-1-one, cyclic GMP protein kinase inhibitor). Protein phosphorylation was determined autoradiographically after gel electrophoresis. In both control and T(4) myocytes, 8-Br-cGMP caused a significant decrease in percent shortening (5.56+/-0.49% to 3.02+/-0.47% in control and 4.34+/-0.33% to 3.13+/-0.17% in T4 myocytes) and maximal rate of contraction 57.35+/-6.05 to 36.82+/-3.17 microm/s in control and 58.49+/-3.28 to 42.88+/-2.29 microm/s in T4 myocytes). KT5823 significantly increased percent shortening to 3.77+/-0.28% and rate to 48.68+/-4.71 microm/s after 8-Br-cGMP only in control myocytes. In T4 myocytes, the changes in percent shortening and rate after KT5823 were not significant. Protein phosphorylation was increased by 8-Br-cGMP in control and to a lesser extent in T4 myocytes, but the increment was reduced by KT-5823 in control only. These data demonstrated that cyclic GMP had negative functional effects partially mediated by cyclic GMP protein kinase in control myocytes. Cyclic GMP also exerted negative functional effects in thyroxine-induced hypertrophic myocytes, but cyclic GMP protein kinase activity was not an important regulator of these effects in T4 ventricular myocytes.

Alkaloids↗
PubMed2001

Intravitreal adenoviral gene transfer evokes an immune response in the retina that is directed against the heterologous lacZ transgene product but does not limit transgene expression.

Recombinant E1-deleted adenoviral vectors (DeltaE1-Ad) are promising tools for in vivo gene transfer into the mammalian CNS including the retina. However, the duration of transgene expression is limited, and this limitation has partly been attributed to an immune response directed against vector-derived proteins. Here, we employed immunocytochemistry to assess the immune response to intravitreously injected DeltaE1-Ad encoding the lacZ gene or various neurotrophins (NTs). beta-Galactosidase was expressed by retinal cells for up to 4 weeks. Following intravitreal inoculation of AdCMV-lacZ, microglial and T cells were detected with a panel of antibodies in the retinal cell layers after 2 days (D2). The inflammatory response reached a maximum between D7 and D14. In contrast, no immune response was seen following injection of Ad encoding NTs. Yet, like with Ad-CMV-lacZ, their expression was also limited to approximately 4 weeks. Thus, beta-galactosidase seems to trigger a host immune response following intravitreal adenoviral lacZ gene transfer, but immune responses are not the cause of limited NT transgene expression from the CMV promoter in the inner retina.

Adenoviridae↗
PubMed2001

Graded expression patterns of ephrin-As in the superior colliculus after lesion of the adult mouse optic nerve.

The idea has been put forward that molecules and mechanisms acting during development are re-used during regeneration in the adult, for example in response to traumatic injury in order to re-establish the functional integrity of neuronal circuits. Members of the Eph family of receptor tyrosine kinases and their 'ligands', the ephrins, play a prominent role during development of the retinocollicular projection in rodents, where EphA receptors and ephrin-As are expressed in gradients in both the retina and the superior colliculi (SC). We were interested in investigating whether EphA family members are also expressed or re-expressed in the adult after optic nerve lesion, since the presence of axon guidance information is an important prerequisite for a topographically appropriate re-connection by retinal ganglion cell (RGC) axons. This analysis was encouraged by results showing that RGC axons do not exert guidance preferences in response to membranes from adult unlesioned SC, but in response to membranes from the adult deafferented SC. We found a graded expression pattern of ephrin-As in the SC both before and after deafferentation, which was remarkably similar to those found during development. EphA receptor levels were reduced in the SC after deafferentation and the expression patterns of the EphB family were not changed. In particular, the presence of a graded ephrin-A expression in the deafferented SC suggests that - if robust regeneration of RGC axons can be achieved - topographic guidance information as a likely requirement for a functionally successful re-establishment of the retinocollicular projection is available.

Animals↗
PubMed2001

Marked suppression of renin levels by beta-receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from beta-blockade.

OBJECTIVES: Recent trials demonstrated beneficial effects of beta-blockers in combination with standard heart failure medication. The mechanisms underlying this benefit are incompletely understood. We hypothesized that beta-blockers may augment the inhibition of the renin-angiotensin system in patients with left ventricular (LV) dysfunction treated with angiotensin-converting enzyme (ACE) inhibitors and/or diuretics by prevention of renin upregulation that occurs in such patients. DESIGN: We examined plasma renin levels (direct radioimmunometric assay) in 312 men with previous myocardial infarction (MI) and echocardiographic LV dysfunction. Patients took medication according to their physicians' prescriptions: antiplatelet agents alone (n=62) or in combination with ACE inhibitors, diuretics or beta-blockers (n=250). RESULTS: Plasma renin levels were elevated in patients taking ACE inhibitors or diuretics and ACE inhibitors plus diuretics (adjusted means from multiple regression analysis were 28.5 mU L-1 [95% CI=20.6-39.5] and 73.7 mU L-1 [95% CI = 49.9- 109.9], respectively) compared with patients on antiplatelets alone (16.1 mU L-1, 95% CI = 13.5-19.3, P < 0.05 each). The combinations of beta-blockers with ACE inhibitors or diuretics and beta-blockers with ACE inhibitors plus diuretics were related to markedly suppressed plasma renin levels (adjusted means 16.4 [13.1-20.6] and 32.1 [23.3-44.3]) as compared with respective patient groups without beta-blockers (P < 0.01 each). CONCLUSIONS: Concomitant beta-blocker treatment can prevent the reactive renin stimulation and potentially the escape from effective inhibition of the renin-angiotensin system in patients with LV dysfunction after MI treated with ACE-inhibitors and/or diuretics.

Adrenergic beta-Antagonists↗
PubMed2001

An improved method of sperm selection by glass wool filtration.

An improved method of sperm selection by glass wool filtration is introduced. After incubation of glass wool filtrates for 30 min at 37 degrees C in a conical-shaped 1.5-ml tube, an enrichment of highly motile spermatozoa was found in the bottom layer of the tube. The effect turned out to be dependent on the conical shape of the tube, as it was not observed in flat-bottomed tubes. Native ejaculates (obtained from 30 men) and their glass wool filtrates were analysed by cell counter, computer-assisted sperm-motility analysis, morphological differentiation and supravital staining of spermatozoa. When 400 microl of ejaculate, diluted with 800 microl of medium, was applied to the top of a column consisting of a 1-ml disposable syringe barrel gently packed with 15 mg of glass wool to a depth of 6 mm, an enrichment of viable spermatozoa was found in the first three 100-microl fractions taken from the bottom of the tube. It is the simplicity of this technique that makes it so easily applicable.

Cell Adhesion↗
PubMed2001

The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction.

AIMS: Prolongation of QT dispersion can be observed in some patients with myocardial infarction and serves as a possible independent risk factor for sudden cardiac death. Angiotensin-converting enzyme (ACE) inhibition has been shown to reduce QT dispersion in myocardial infarction patients. We hypothesized that ACE gene I/D polymorphism, which is known to modulate ACE activity, may also affect QT dispersion after myocardial infarction. METHODS AND RESULTS: We studied 609 myocardial infarction patients (532 men, aged 56.1+/-0.3; mean 5.5 years after myocardial infarction) from a population-based myocardial infarction register by standardized questionnaire, anthropometry, ECG, echocardiography, and genotyping of ACE I/D polymorphism. In addition, 540 unaffected siblings (251 men, age 54.6+/-0.4 years) of these patients were studied by the same protocol. As compared with their healthy siblings, mean QT dispersion was prolonged in myocardial infarction patients (65.9+/-1.4 ms vs 91.2+/-2.3 ms, respectively, P<0.001). QT dispersion was negatively correlated to left ventricular ejection fraction (P<0.005). The ACE DD-genotype was associated with longer QT dispersion in myocardial infarction patients (103.0+/-4.6 ms vs 81.9+/-4.5 ms in the II group, P<0.001). This association was noted to be strong in multivariate analyses that included age, gender, ejection fraction, left ventricular end-diastolic diameter, medication, and heart rate. In contrast, no association between the ACE DD-genotype and QT dispersion was detected in healthy siblings of myocardial infarction patients. CONCLUSION: Thus, the ACE D-allele may be associated with increased QT dispersion in patients after myocardial infarction but not in healthy subjects. An interaction of myocardial damage and genetic predisposition that both enhance the activity of the renin angiotensin system may decrease the repolarization homogeneity of the heart.

Alleles↗
PubMed2001

Siblings of myocardial infarction patients are overlooked in primary prevention of cardiovascular disease.

AIMS: Patients with arterial hypertension or hypercholesterolaemia may benefit from medical therapy for primary prevention of myocardial infarction. Preventive therapy may be particularly effective in individuals with a positive family history for myocardial infarction since such subjects are at high risk for coronary events. The objective of this population-based study was to analyse the risk profile as well as the current utilization of preventive strategies in asymptomatic siblings of patients with myocardial infarction. METHODS AND RESULTS: We studied siblings of 325 patients with premature myocardial infarction from the Augsburg MONICA myocardial infarction registry by standardized questionnaire, blood pressure recordings, and biochemical measurements. Out of 580 siblings, 510 were free of coronary heart disease symptoms. With multiple risk factors being present in most asymptomatic siblings, 29.4% of asymptomatic individuals had an estimated individual 10-year risk for a major cardiovascular event of > or = 20%, or when projected to the age of 60. According to the guidelines of the European Societies of Cardiology, Atherosclerosis, and Hypertension (ESC/EAS/ESH) from 1994 (1998 guidelines in parenthesis) dietary and lifestyle interventions were indicated for arterial hypertension in 48.1% (43.0%) and/or for hypercholesterolaemia in 17.3% (78.8%). Drug treatment was indicated for arterial hypertension in 27.9% (30.6%) and for hypercholesterolaemia in 13.6% (19.1%) of asymptomatic siblings. Of those individuals with the respective indication, actual drug treatment was given for arterial hypertension in 91.5% (83.3%) and for hypercholesterolaemia in 46.4% (33.0%). However, treatment targets were reached in only 31.0% (28.2%) with arterial hypertension and in 7.2% (5.2%) with hypercholesterolaemia, respectively. CONCLUSIONS: Most asymptomatic individuals with positive fraternal family history have more than one modifiable risk factor. Interestingly, a large number of these individuals appears to be under medical surveillance as many receive some sort of drug treatment. However, this therapy did not meet the treatment goals in the majority of those with arterial hypertension and/or hypercholesterolaemia. Thus, although individuals with a positive fraternal history for myocardial infarction can be easily identified, implementation of sufficient preventive strategies continues to be poor in a Western European country.

Adult↗
PubMed2000

Determination of the dissociation constant of valine from acetohydroxy acid synthase by equilibrium partition in an aqueous two-phase system.

An aqueous polyethylene glycol/salt two-phase system was used to estimate the dissociation constant, K(dis), of the Escherichia coli isoenzyme AHAS III regulatory subunit, ilvH protein, from the feedback inhibitor valine. The amounts of the bound and free radioactive valine in the system were determined. A Scatchard plot of the data revealed a 1:1 valine-protein binding ratio and K(dis) of 133+/-14 microM. The protein did not bind leucine, and the ilvH protein isolated from a valine resistant mutant showed no valine binding. This method is very simple, rapid and requires only a small amounts of protein compared to the presently used equilibrium dialysis method.

Acetolactate Synthase↗
PubMed2000

Purification of acetohydroxy acid synthase by separation in an aqueous two-phase system.

Extraction in a polyethylene glycol (PEG)-phosphate aqueous two-phase system was considered as a primary step in purification of the acetohydroxy acid synthase III large catalytic subunit from an E. coli extract. Extraction optimization was achieved by varying the system parameters. Two systems with the following weight compositions were chosen for purification: PEG-2000 (16%)-phosphate (6%) and PEG-4000 (14%)-phosphate (5.5%)-KCl (8%), both at pH 7.0 and 1 mg total protein per 1 g system. Significant purification was achieved by a single extraction step with 70% recovery of the enzyme. After an additional ion-exchange chromatography step, pure enzyme was obtained in a 50% overall yield.

Acetolactate Synthase↗
PubMed2000

The impact of diabetes mellitus on survival after myocardial infarction: can it be modified by drug treatment? Results of a population-based myocardial infarction register follow-up study.

AIMS/HYPOTHESIS: Mortality of diabetic patients after myocardial infarction remains high despite recent improvement in their management. This study population-based evaluates the impact of cardiovascular drug therapy on mortality within 28 days and during 5-year follow-up in diabetic compared with non-diabetic patients. METHODS: Using the MONICA Augsburg register from 1985 to 1992, 2210 inpatients with incident Q-wave myocardial infarction aged 25-74 years were included, of whom 468 had diabetes. Primary end point was mortality within 28 days and over 5 years. General linear model procedures were used for age-adjustment, controlling for sex, and testing significance; hazard risk ratios were calculated using multivariable Cox proportional hazards model procedures. RESULTS: During the 5-year follow-up, 598 subjects died (396 diabetic, 202 non-diabetic). The mortality rate within 28 days was 12.6% in diabetic patients (women 18.0%, men 9.9%) and 7.3% in non-diabetic patients (p = 0.001). Mortality in diabetic patients over 5 years was increased by 64% (95% confidence interval 1.39-1.95) compared with non-diabetic patients. This was considerably reduced (p < 0.001) in patients treated with thrombolytic drugs (risk ratio: diabetes 0.57, no diabetes 0.65) and with beta blockers (0.62 and 0.64) and antiplatelets (0.76 and 0.74) at hospital discharge. Mortality of diabetic patients treated with these drugs was reduced to that of non-diabetic patients without such treatment (risk ratio 1.01 to 1.27; p > 0.1). CONCLUSION/INTERPRETATION: Diabetic patients after myocardial infarction are at particularly high risk of dying, but benefit clearly from treatment with thrombolytics, beta blockers and antiplatelets. This study does not, however, allow any inferences to be drawn for treatment with angiotensin converting enzyme inhibitors or the impact of left ventricular function.

Adrenergic beta-Antagonists↗
PubMed2000

Differential regulation of the monocytic calcium-binding peptides macrophage-inhibiting factor related protein-8 (MRP8/S100A8) and allograft inflammatory factor-1 (AIF-1) following human traumatic brain injury.

Intracellular calcium (Ca2+) has been shown to function as second messenger and to be associated with activation of different cell types including microglia. Previously, in human focal cerebral infarctions an early expression of macrophage-related protein-8 (MRP8/ S100A8), a member of the Ca2+-binding S100-protein family, in microglia has been reported. On the other hand, a delayed activation of microglia was observed following traumatic brain injury (TBI). We therefore examined immunohistochemically microglial expression of MRP8 and allograft inflammatory factor-1 (AIF-1), identical to microglial response factor-1 (mrf-1) and ionized calcium binding adaptor molecule-1 (ibal) in human brains after TBI and in control brains. Both, MRP8 and AIF-1 are Ca2+-binding peptides which have been associated with microglial activation in experimental models and in human cerebral infarctions. Detection of AIF-1 in controls confirmed constitutive expression of this peptide in a subset of microglial cells. After TBI, the density of AIF-1+ microglia did not increase significantly. Lesional expression of AIF-1 did not significantly differ from other brain regions. Furthermore, following TBI, we found no significant differences in the density of AIF-1+ microglia as compared to controls. Microglial MRP8 expression was not detectable in controls and within the first 3 days post TBI, but increased rapidly after 3 days post TBI, suggesting a subpopulation of microglial cells to be AIF-1-/MRP8+. We conclude that the delayed expression of MRP8 and the lack of AIF-1 up-regulation in microglia after TBI is in contrast to ischemic brain lesions and might reflect different activation cascades of microglia.

Adolescent↗
PubMed2000

Allograft inflammatory factor-1 defines a distinct subset of infiltrating macrophages/microglial cells in rat and human gliomas.

Allograft inflammatory factor-1 (AIF-1) is a Ca2+-binding peptide that constitutes a potential modulator of macrophage activation and function during the immune response of the brain. Peptides termed microglia response factor-1 or ionized calcium-binding adaptor molecule- have been reported to be identical with AIF-1. We have investigated the expression of AIF-1 in the rat C6 glioblastoma and 9L gliosarcoma tumor models and additionally assessed AIF- expression in a diverse range of human astrocytomas by immunohistochemistry. AIF-1 was expressed by activated microglial cells and a subset of infiltrating macrophages in areas of infiltrative tumor growth and in compact tumor areas in both rat and human gliomas. Double-labeling experiments in rats and humans characterized the nature and the functional status of AIF-1+ cells. AIF-1 expression was detected in cells expressing major histocompatibility complex class II molecules and in a subset of activated macrophages/microglial cells. All MRP-8+ cells coexpressed AIF-1. In humans, there was a strong correlation of AIF-1-expressing activated macrophages/microglial cells with tumor malignancy (P < 0.0001). These results suggest that AIF-1 defines a distinct subset of tumor-associated activated macrophages/ microglial cells.

Adult↗
PubMed2000

Dynamics of microglial activation after human traumatic brain injury are revealed by delayed expression of macrophage-related proteins MRP8 and MRP14.

Human traumatic brain injury (TBI) is ideally suited for investigation of the kinetics of human microglial cell activation as the onset of lesion formation is precisely defined. The present study provides evidence of a distinct delay in macrophage/microglia response following TBI. Eighteen brains of patients who had survived TBI for 1 h to 6 months were analysed by immunohistology. Samples of contusional and non-contusional areas were studied using antibodies directed against antigens of microglia/ macrophages [major histocompatibility complex class II, CD4, interleukin (IL)-16, macrophage-related protein (MRP) 8 and MRP14]. IL-16, a natural ligand to CD4, was expressed constitutively by numerous microglial cells in all cases throughout the brain. CD4 could be detected regularly on perivascular cells. MRP8 and MRP14, which are only expressed on activated macrophages and microglial cells, could be detected only within brains with a survival time of more than 72 h post TBI. In addition, proliferation of microglia detected by MIB-1 was not present until 72 h. This delayed expression of the activation markers MRP8 and MRP14 and the proliferation marker MIB-1 is comparable to experimental closed head injuries but strictly different from acute activation found in ischemic brains.

Adolescent↗