Showing papers by "University of Graz published in 1999"

Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds

Abstract: BACKGROUND AND PURPOSE: Patients with spontaneous intracerebral hemorrhage (ICH) frequently have small areas of signal loss on gradient-echo T2*-weighted MR images, which have been suggested to represent remnants of previous microbleeds. Our aim was to provide histopathologic support for this assumption and to clarify whether the presence and location of microbleeds were associated with microangiopathy. METHODS: We performed MR imaging and correlative histopathologic examination in 11 formalin-fixed brains of patients who had died of an ICH (age range, 45–90 years). RESULTS: Focal areas of signal loss on MR images were noted in seven brains. They were seen in a corticosubcortical location in six brains, in the basal ganglia/thalami in five, and infratentorially in three specimens. Histopathologic examination showed focal hemosiderin deposition in 21 of 34 areas of MR signal loss. No other corresponding abnormalities were found; however, hemosiderin deposits were noted without MR signal changes in two brains. All specimens with MR foci of signal loss showed moderate to severe fibrohyalinosis, and there was additional evidence of amyloid angiopathy in two of those brains. CONCLUSION: Small areas of signal loss on gradient echo T2*-weighted images indicate previous extravasation of blood and are related to bleeding-prone microangiopathy of different origins.

Enzymatic function of nitric oxide synthases.

Abstract: Nitric oxide (NO) is synthesised from l-arginine by the enzyme NO synthase (NOS). The complex reaction involves the transfer of electrons from NADPH, via the flavins FAD and FMN in the carboxy-terminal reductase domain, to the haem in the amino-terminal oxygenase domain, where the substrate l-arginine is oxidised to l-citrulline and NO. The haem is essential for dimerisation as well as NO production. The pteridine tetrahydrobiopterin (BH4) is a key feature of NOS, affecting dimerisation and electron transfer, although its full role in catalysis remains to be determined. NOS can also catalyse superoxide anion production, depending on substrate and cofactor availability. There are three main isoforms of the enzyme, named neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS), which differ in their dependence on Ca2+, as well as in their expression and activities. These unique features give rise to the distinct subcellular localisations and mechanistic features which are responsible for the physiological and pathophysiological roles of each isoform.

Squeezing the Optical Near-Field Zone by Plasmon Coupling of Metallic Nanoparticles

Abstract: We report on the experimental observation of near-field optical effects close to Au nanoparticles using a photon scanning tunneling microscope (PSTM). Constant height operation of the PSTM allowed an unprecedented direct comparison with theoretical computations of the distribution of the optical near-field intensity. An unexpected squeezing of the optical near field due to plasmon coupling was observed above a chain of Au nanoparticles.

Event-related EEG/MEG synchronization and desynchronization: Basic principles

Abstract: An internally or externally paced event results not only in the generation of an event-related potential (ERP) but also in a change in the ongoing EEG/MEG in form of an event-related desynchronization (ERD) or event-related synchronization (ERS). The ERP on the one side and the ERD/ERS on the other side are different responses of neuronal structures in the brain. While the former is phase-locked, the latter is not phase-locked to the event. The most important difference between both phenomena is that the ERD/ERS is highly frequency bandspecific, whereby either the same or different locations on the scalp can display ERD and ERS simultaneously. Quantification of ERD/ERS in time and space is demonstrated on data from a number of movement experiments. q 1999 Elsevier Science Ireland Ltd. All rights reserved.

Control of the Burgers equation by a reduced-order approach using proper orthogonal decomposition

Abstract: Proper orthogonal decomposition (POD) is a method to derive reduced-order models for dynamical systems In this paper, POD is utilized to solve open-loop and closed-loop optimal control problems for the Burgers equation The relative simplicity of the equation allows comparison of POD-based algorithms with numerical results obtained from finite-element discretization of the optimality system For closed-loop control, suboptimal state feedback strategies are presented

MRI evidence of past cerebral microbleeds in a healthy elderly population.

Abstract: Background: Incidental foci of signal loss suggestive of past microbleeds are a frequent finding on gradient-echo T2*-weighted MRI of patients with nontraumatic intracerebral hemorrhage and have been associated with bleeding-prone microangiopathy. If and to what extent such lesions may also occur in the normal population is unclear. Objective: To determine focal hypointensities in asymptomatic elderly individuals and their relation to other clinical and morphologic variables. Methods: T2*-weighted MRI of the brain was performed in a consecutive series of 280 participants (mean age 60 years, range 44 to 79) of the Austrian Stroke Prevention Study. This cohort consisted of randomly selected individuals without history or signs of neuropsychiatric disorder. Results: Past microbleeds ranging from one to five foci of signal loss were seen in 18 (6.4%) individuals. They were strongly associated with higher age, hypertension, and lacunes ( p p = 0.02). Hypertension was present in all individuals with focal hypointensities in the basal ganglia and infratentorially but in only 5 of 10 volunteers with microbleeds limited to cortico-subcortical sites ( p = 0.04). Conclusions: MRI evidence of past microbleeds may be found even in neurologically normal elderly individuals and is related, but not restricted, to other indicators of small vessel disease. The predictive potential of this finding regarding the risk of intracerebral bleeding requires further investigation.

Linear Assignment Problems and Extensions

Abstract: Assignment problems deal with the question how to assign n items (eg jobs) to n machines (or workers) in the best possible way They consist of two components: the assignment as underlying combinatorial structure and an objective function modeling the ”best way”

MRI white matter hyperintensities: Three-year follow-up of the Austrian Stroke Prevention Study

Abstract: Objective: To determine the rate, clinical predictors, and cognitive consequences of MRI white matter hyperintensity evolution over 3 years. Methods: In the setting of the Austrian Stroke Prevention Study, 1.5-T MRI was performed at baseline and at a 3-year follow-up in 273 community-dwelling elderly (mean age, 60 ± 6.1 years) without neuropsychiatric disease. At each visit individuals underwent a structured clinical interview and examination, EKG, echocardiography, extensive laboratory workup, and demanding neuropsychological testing. MR images were read by three independent raters, and the change of white matter hyperintensities from baseline was assessed by direct image comparison. The change was graded as absent, minor, or marked. Minor change was defined as a difference of no more than one to four punctate lesions between both scans. A change was considered to be marked if there was a difference of more than four abnormalities or a transition to early-confluent and confluent lesions. Results: Combined ratings indicated lesion progression in 49 individuals (17.9%). Lesion progression was minor in 27 participants (9.9%) and was marked in 22 (8.1%). Regression of white matter hyperintensities did not occur. Diastolic blood pressure (odds ratio, 1.07/mm Hg) and early-confluent or confluent white matter hyperintensities at baseline (odds ratio, 2.62) were the only significant predictors of white matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychological test performance over the observational period. Conclusions: White matter hyperintensities progress in elderly normal subjects. Our data may be used as a reference for future observational and interventional studies on white matter hyperintensity progression in various CNS diseases. The lack of an association between lesion progression and cognitive functioning needs to be explored further.

Crystal structure of human β2‐glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome

Abstract: The high affinity of human plasma beta2-glycoprotein I (beta(2)GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. beta(2)GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the beta(2)GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans. The structure reveals four complement control protein modules and a distinctly folding fifth C-terminal domain arranged like beads on a string to form an elongated J-shaped molecule. Domain V folds into a central beta-spiral of four antiparallel beta-sheets with two small helices and an extended C-terminal loop region. It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313-316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances. The beta(2)GPI structure reveals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid-binding capacity of beta(2)GPI.

Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact.

Abstract: Membrane association between mitochondria and the endoplasmic reticulum of the yeast Saccharomyces cerevisiae is probably a prerequisite for phospholipid translocation between these two organelles. This association was visualized by fluorescence microscopy and computer-aided three-dimensional reconstruction of electron micrographs from serial ultrathin sections of yeast cells. A mitochondria-associated membrane (MAM), which is a subfraction of the endoplasmic reticulum, was isolated and re-associated with mitochondria in vitro. In the reconstituted system, phosphatidylserine synthesized in MAM was imported into mitochondria independently of cytosolic factors, bivalent cations, ATP, and ongoing synthesis of phosphatidylserine. Proteolysis of mitochondrial surface proteins by treatment with proteinase K reduced the capacity to import phosphatidylserine. Phosphatidylethanolamine formed in mitochondria by decarboxylation of phosphatidylserine is exported to the endoplasmic reticulum where part of it is converted into phosphatidylcholine. In contrast with previous observations with permeabilized yeast cells [Achleitner, G., Zweytick, D., Trotter, P., Voelker, D. & Daum, G. (1995) J. Biol. Chem.270, 29836–29842], export of phosphatidylethanolamine from mitochondria to the endoplasmic reticulum was shown to be energy-independent in the reconstituted yeast system.

PTEN Is Inversely Correlated With the Cell Survival Factor Akt/PKB and Is Inactivated Via Multiple Mechanisms in Haematological Malignancies

Abstract: PTEN is a novel tumour suppressor gene that encodes a dual-specificity phosphatase with homology to adhesion molecules tensin and auxillin. It recently has been suggested that PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3, 4,5)P3], which mediates growth factor-induced activation of intracellular signalling, in particular through the serine-threonine kinase Akt, a known cell survival-promoting factor. PTEN has been mapped to 10q23.3, a region disrupted in several human tumours including haematological malignancies. We have analysed PTEN in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs) as well as in cell lines. We have also examined whether a correlation could be found between PTEN and Akt levels in these samples. We show here that the majority of cell lines studied carries PTEN abnormalities. At the structural level, we found mutations and hemizygous deletions in 40% of these cell lines, while a smaller number of primary haematological malignancies, in particular NHLs, carries PTEN mutations. Moreover, one-third of the cell lines had low PTEN transcript levels, and 60% of these samples had low or absent PTEN protein, which could not be attributed to gene silencing by hypermethylation. In addition, we found that PTEN and phosphorylated Akt levels are inversely correlated in the large majority of the examined samples. These findings suggest that PTEN plays a role in the pathogenesis of haematological malignancies and that it might be inactivated through a wider range of mechanisms than initially considered. The finding that PTEN levels inversely correlate with phosphorylated Akt supports the hypothesis that PTEN regulates PtdIns(3,4,5)P3and suggests a role for PTEN in apoptosis.

The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis

Abstract: MRI is very sensitive in showing MS lesions throughout the CNS Using MRI for diagnostic purposes, however useful, is a complex issue because of limited specificity of findings and a variety of options as to when, how, and which patients to examine Comparability of data and a common view regarding the impact of MRI are needed Following a review of the typical appearance and pattern of MS lesions including differential diagnostic considerations, we suggest economic MRI examination protocols for the brain and spine Recommendations for referral to MRI consider the need to avoid misdiagnosis and the probability of detecting findings of diagnostic relevance We also suggest MRI classes of evidence for MS to determine the diagnostic weight of findings and their incorporation into the clinical evaluation These proposals should help to optimize and standardize the use of MRI in the diagnosis of MS

Functions of c-Jun in Liver and Heart Development

Abstract: The proto-oncogene c-jun encodes a component of the transcription factor AP-1 (activating protein 1)1, which has been implicated in the regulation of diverse cellular functions, such as proliferation, differentiation, transformation, and apoptosis. AP-1 is a dimer consisting of different subunits, e.g., proteins of the Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra1, and Fra2) family as well as CREB/ATF, and Maf proteins. The different AP-1 components are expressed in a development- and tissue-specific manner, implying that AP-1 composed of different subunits may exert different functions in different cell types. Although AP-1 was found to regulate a few genes, such as human metallothionein IIA (Lee et al., 1987), collagenase (Angel et al., 1987), stromelysin (Kerr et al., 1988), and keratin 18 (Oshima et al., 1990), the biological function of the different AP-1 complexes during development is still elusive. The characterization of the role of AP-1 is further impeded by the fact that there are, in addition to the variability in subunit composition, numerous possible interactions between AP-1 and other transcription factors, such as glucocorticoid hormone receptors (Jonat et al., 1990), estrogen receptors (Gaub et al., 1990), retinoic acid and vitamin D3 receptors (Schule et al., 1990), and MyoD (Bengal et al., 1992) yielding a network of transcriptional regulation. First clues on tissue-specific functions of AP-1 components came from gene knockout experiments. In c-fos knockout mice the development of bone is impaired because of a block in osteoclast differentiation (Grigoriadis et al., 1994). Moreover, lymphoid cells, germ cells, and neuronal tissues are affected in the absence of c-Fos (Johnson et al., 1992; Wang et al., 1992). In contrast to the inactivation of c-fos, targeted disruption of c-jun and junB is lethal (Hilberg et al., 1993; Johnson et al., 1993; Schorpp-Kistner et al., 1999). Lethality of c-jun−/− fetuses has been suggested to be due to defective liver development. The livers of some E12.5 animals appeared hypoplastic with rounded, dissociated hepatoblasts showing features of apoptosis and necrosis. Moreover, increased numbers of erythropoietic cells were noted in these livers (Hilberg et al., 1993). A defect in hepatogenesis in c-Jun knockout mice was further indicated by the observation that c-jun−/− embryonic stem (ES) cells failed to contribute to the liver but not to other tissues of adult chimeric mice (Hilberg et al., 1993). These observations, together with the fact that no morphological alterations were found in organs other than the liver, led to the conclusion that the absence of c-Jun might preferentially affect the development of the liver (Hilberg et al., 1993). In the mouse, liver development starts at around E9.5 when epithelial cells of the foregut endoderm proliferate and invade the mesenchyme of the septum transversum thus forming the embryonic liver. At around E11 hematopoietic stem and progenitor cells derived from the yolk sac and aorta-gonad-mesonephros region colonize the liver, and the liver becomes the major hematopoietic organ during further fetal development (Dzierzak and Medvinsky, 1995). To allow establishment and maintenance of hematopoiesis, liver cells have to provide the proper microenvironment for hematopoietic cells comparable to stromal cells in the bone marrow during postnatal life. The next major step in mouse liver development occurs at approximately E14.5 when hepatoblasts start to differentiate into the hepatocytic and bile duct epithelial lineage, which is indicated by the formation of the ductal plate, which later differentiates into the intrahepatic bile ducts (Desmet, 1998). It is as yet unclear at which developmental stage c-Jun becomes essential for the liver, and whether the defect is restricted to the hepatocytic lineage or other cell types of the fetal liver, such as bile duct epithelia, endothelial cells, stellate cells (vitamin A–storing cells), Kupffer cells, and hematopoietic cells. Besides the poorly characterized function in liver development, c-Jun plays a more general role in the regulation of cell proliferation and apoptosis. It has been shown in fibroblasts isolated from E11.5 c-jun−/− and c-jun+/− embryos that the absence or diminished expression of c-Jun resulted in greatly reduced growth rates, and that this proliferation defect could not be compensated by addition of purified mitogens (Johnson et al., 1993; Schreiber et al., 1999). Evidence for a role of c-Jun and c-Jun phosphorylation in apoptosis was obtained in neuronal cells where transient overexpression of c-Jun induced apoptosis, and expression of a dominant negative c-jun mutant inhibited apoptosis in vitro (Estus et al., 1994; Ham et al., 1995; Behrens et al., 1999). In vivo, however, c-Jun was regarded not to be essential for apoptosis since in the developing mouse (E11.5 c-jun−/− fetuses) the physiologically occurring apoptosis appeared unaffected (Roffler-Tarlov et al., 1996). The different phenotypes observed in the various AP-1 knockout mice point to cell type– and developmental-specific roles of AP-1 complexes. The biological basis for the specific roles is not yet understood. To gain more insight into how the absence of a widely expressed transcription factor like c-Jun affects the liver, and to see whether other tissues are affected, we investigated in detail the morphological and functional alterations in c-jun knockout mice as well as the distribution of c-jun−/− cells in chimeric mice at various stages during fetal development and postnatal life. A deregulation of apoptosis was found in a variety of cell types lacking c-jun, such as hepatoblasts, erythroid cells, and fibroblasts. In contrast to previous reports that suggested that c-Jun is essential for cells to undergo apoptosis, we observed markedly increased apoptotic rates in the absence of c-Jun. It is possible that an increased susceptibility of cells to apoptosis was responsible for the morphologic alterations seen in the livers of c-jun−/− mice. Increased apoptotic rates in combination with reduced proliferation rates would result in a disturbance of hepatocyte turnover which could explain the absence of c-jun−/− hepatocytes in livers of adult chimeric mice. Furthermore, a novel function of c-Jun in heart development was identified, since all c-jun−/− fetuses had a malformation of the outflow tract of the heart which could be a contributing factor to the fetal lethality.

Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy.

Abstract: Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy

Event-Related changes of band power and coherence: methodology and interpretation.

Abstract: SummaryEvent-related calculation of band power changes can be used to quantify event-related desynchronization, event-related synchronization, and event-related coherence (ERCoh). It is shown that in the case of a motor task especially, the ERCoh time course depends on the type of EEG derivation use

Small-angle scattering of interacting particles. II. Generalized indirect Fourier transformation under consideration of the effective structure factor for polydisperse systems

Abstract: The indirect Fourier transformation (IFT) is the method of choice for the model-free evaluation of small-angle scattering data Unfortunately, this technique is only useful for dilute solutions because, for higher concentrations, particle interactions can no longer be neglected Thus an advanced technique was developed as a generalized version, the so-called generalized indirect Fourier transformation (GIFT) It is based on the simultaneous determination of the form factor, representing the intraparticle contributions, and the structure factor, describing the interparticle contributions The former can be determined absolutely free from model assumptions, whereas the latter has to be calculated according to an adequate model In this paper, various models for the structure factor are compared, eg the effective structure factor for polydisperse hard spheres, the averaged structure factor, the local monodisperse approximation and the decoupling approximation Furthermore, the structure factor for polydisperse rod-like particles is presented As the model-free evaluation of small-angle scattering data is an essential point of the GIFT technique, the use of a structure factor without any influence of the form amplitude is advisable, at least during the first evaluation procedure Therefore, a series of simulations are performed to check the possibility of the representation of various structure factors (such as the effective structure factor for hard spheres or the structure factor for rod-like particles) by the less exact but much simpler averaged structure factor In all the observed cases, it was possible to recover the exact form factor with a free determined parameter set for the structure factor The resulting parameters of the averaged structure factor have to be understood as apparent model parameters and therefore have only limited physical relevance Thus the GIFT represents a technique for the model independent evaluation of scattering data with a minimum of a priori information

Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B

Abstract: Dysferlin deletion in SJL mice (SJL- Dysf ) defines a natural model for limb girdle muscular dystrophy 2B

Influence of beta-blockers on melatonin release.

Abstract: Objective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before.

Resonant and Off-Resonant Light-Driven Plasmons in Metal Nanoparticles Studied by Femtosecond-Resolution Third-Harmonic Generation

Abstract: We report on a femtosecond-resolution study of the plasmon fields in gold nanoparticles using third-harmonic generation. Controlled resonant and off-resonant plasmon excitation is achieved by tailoring the nanoparticle sample by an electron-beam-lithographic method. Comparing the measured third order interferometric autocorrelation function of the plasmon field with simulations based on a simple harmonic oscillator model we extract the temporal characteristic of the plasmon oscillation. For off-resonant excitation of particle plasmons we find a beating between the driving laser field and the plasmon field which demonstrates clearly the nature of the plasmon as a collective electron oscillation.

The functionality of HLA-G is emerging.

Abstract: Summary: In view of the recently published data, the HLA-G class Ib gene appears to be a functional locus. This is based on the following observations: 1) HLA-G is capable of presenting nonamer peptides and of exerting antigen-presenting functions; 2) HLA-G is a ligand for at least three natural killer (NK) and other cell inhibitory receptors of the immunoglobulin superfamily, namely leukocyte immunoglobulin-like receptor-1 /immunoglobulin-like transcript (ILT)-2, ILT-4 and p49; 3) in addition to the extravillous cytotrophoblast cells, HLA-G proteins have been detected in endothelial cells of placental chorionic villi, as well as in amniotic fluid and in some medullary thymic epithelial cells; 4) major histocompatibility complex (MHC) class Ib genes that share the unique characteristics of HLA-G, including a high expression in placenta, have been reported in other mammalian species. In addition to the classical MHC class I roles (antigen presentation and ligarion to NK receptors inducing inhibitory and/or activatory signals), HLA-G is likely to exert other, novel functions: first, HLA-G was shown to be involved in the control of HLA-E expression by furnishing the appropriate class I leader sequence nonamer peptide; second, we hypothesize that HLA-G could be a regulator of placental angiogenesis; third, soluble HLA-G isoforms may act as specific immunosuppressors during pregnancy. Such functional properties, although incompletely understood, are likely to be important in the outcome of human pregnancies but also in normal adult life.

Variances of GPS Phase Observations: The SIGMA-ɛ Model

Abstract: The noise term of GPS phase data can be calculated from the measured carrier-to-noise power density ratios (C/N0). The C/N0 values are used in the proposed SIGMA-ɛ model to calculate the variance matrix of double-differenced GPS phase data. Examples show the capability of this model to yield higher accuracies for GPS surveys than the use of the standard weighting scheme. Most importantly, the SIGMA-ɛ model allows the use of noisier phase data from very low elevation satellites to overcome poor satellite geometry problems. © 1999 John Wiley & Sons, Inc.

A Third Major Locus for Autosomal Dominant Hypercholesterolemia Maps to 1p34.1-p32

Abstract: Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted.

Specific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria.

Abstract: Background: Few recent studies have analyzed the clinicopathologic features of specific cutaneous manifestations of myelogenous leukemia in a large number of patients Objective: We characterize the clinical and histopathologic spectrum of specific cutaneous manifestations in acute (AML) and chronic (CML) myelogenous leukemia, ascertain further diagnostic criteria, and examine current prognosis Methods: Thirty-six lesions of specific cutaneous infiltrates from 26 patients with my-elogenous leukemia (AML: 17 patients; M:F = 1:24; mean age: 526 years; AML-French-American-British [FAB] classification subtypes:M1 =1, M2=3, M4=8, M5=5 CML=9 patients; M:F = 45:1; mean age: 606 years) were retrospectively collected for the study Results: Cutaneous manifestations presented as solitary or multiple reddish to violaceous papules, plaques, and nodules (17 lesions), or as a generalized erythematous maculopapular eruption (9 lesions) Concurrent extramedullary involvement in other peripheral sites (eg, gums, pharynx, orbits) was observed in 10 patients Histopathologically, lesions revealed nodular/diffuse infiltrates, often with perivascular and periadnexal accentuation, sparing of the upper papillary dermis, and prominent single arraying of neoplastic cells between collagen bundles Extension to the subcutis was noted in all deep biopsy specimens (26 lesions) Cytomorphologically, medium to large-sized mononuclear cells (myeloblasts and atypical myelocytes) predominated in AML-M1 and M2, whereas M4 and M5 mainly showed small, medium-sized, or large mononuclear cells with slightly eosinophilic cytoplasm and indented, bi-lobular, or kidney-shaped nuclei (atypical monocytoid cells) In CML, either a variable mixture of mature and immature cells of the granulocytic series (myelocytes, metamyelocytes, eosinophilic metamyelocytes, and neutrophils) or a rather monomorphous infiltrate of mononuclear cells were found Staining for naphthol AS-D chloroacetate-esterase (NASD) was positive in 24 of 36 lesions (666%; AML: 16; CML: 8) Immunohistochemical analysis on paraffin sections using a large panel of antibodies (16 lesions: AML: 13; CML: 3) showed strong reactivity for LCA (CD45), lysozyme, myeloperoxidase (MPD), LN2 (CD74), HLA-DR, and MT1 (CD43) in the majority of cases, and variable staining for monocyte/macrophage markers (KP1/CD68, PGM1/CD68, Mac387, Ki-M1p) The neuronal cell adhesion molecule (N-CAM) marker CD56 was reactive in 2 cases of CML, but negative in all cases of AML MIB1(Ki67) stained 20% to 80% of neoplastic cells CD34, CD15, CD20, and CD3 were negative in all cases No correlation between histochemical/immunohistochemical features with type of leukemia or FAB-subtype of AML was observed All patients with CML and AML with adequate follow-up died within 24 months after onset of skin lesions (mean survival, AML: 76 months; CML: 94 months) Conclusion: Specific cutaneous lesions in AML and CML show distinctive clinicopathologic features that allow diagnosis in most cases Immunohistochemistry on routinely fixed, paraffin-embedded tissue sections provides useful adjunctive information Simultaneous expression of lysozyme, MPD, CD45, CD43, and CD74 militates in favor of a diagnosis of specific cutaneous infiltrate of myelogenous leukemia Pitfalls in immunohistologic diagnosis mainly include lack of expression of some myeloid markers (lysozyme, MPD), and aberrant expression of T-cell markers (eg, CD45RO) Regardless of type of myelogenous leukemia, onset of specific skin manifestations correlates with an aggressive course and short survival (J Am Acad Dermatol 1999;40:966-78)

β-2 Adrenergic Receptor Variants Affect Resting Blood Pressure and Agonist-Induced Vasodilation in Young Adult Caucasians

Abstract: Recent evidence suggests that the prodownregulatory Gly16 allele of the beta-2 adrenergic receptor (beta-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 beta-2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m2, were genotyped for the Arg16/Gly16 beta-2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects' genotypes. The subjects received a graded infusion of the selective beta-2 AR agonist salbutamol (0.07, 0.14, and 0.21 microgram/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (mean+/-SD: 81.6+/-6.14 versus 75.2+/-4.93 mm Hg, P<0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (Deltatotal peripheral resistance index -17.9+/-14.4 versus -30. 6+/-8.3%, P<0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (Deltaheart rate +16.9+/-7.0% versus +8.6+/-7. 0%, P<0.01; Deltacardiac index +39.5+/-18.5% versus 21.4+/-18.8%, P<0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the beta-2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension.