[Congenital vascular malformations (Hauert disease)]. / Angiodysplastische Arthropathie ("Hauert disease").

Patients with congenital vascular malformations often suffer from arthralgia, especially of the lower limbs. This orthopaedic disease pattern is defined as destructive, angiodysplatic arthritis or Hauert disease and leads to very early destruction of the joints. By presenting diagnostic and therapeutic algorithms, Hauert disease is emphasized as a possible differential diagnosis in order to minimize the risk of an incorrect diagnosis which might lead to under-, over-, or even incorrect treatment. A minimally invasive transathroscopic therapy in the early stages can lead to significant improvement of symptoms and prevention of progressive joint destruction.

An estrogen-binding protein and endogenous ligand in Saccharomyces cerevisiae: possible hormone receptor system.

A protein macromolecule in the cytosol of the unicellular eukaryotic yeast Saccharomyces cerevisiae selectively binds the vertebrate estrogen hormone 17 beta-estradiol with high affinity. Lipid extracts of the yeast cells or the conditioned growth medium yield a substance that can bind competitively to the tritiated estradiol-binding sites in the yeast and to mammalian estrogen receptors. These findings suggest that the binding protein may be a primitive hormone receptor and that the lipid-extractable substance represents the endogenous ligand.

Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells.

We have recently found that ketoconazole inhibits adrenal steroidogenesis; in this paper we investigated whether imidazole antimycotic drugs additionally interact with glucocorticoid receptor sites in target tissues. Our approach was to assess the ability of three drugs: ketoconazole, clotrimazole, and RS 49910, to inhibit [3H]dexamethasone binding to hepatoma tissue culture (HTC) cell cytosol. The results indicated dose-dependent, competitive displacement of [3H]dexamethasone binding that was in the potency sequence: clotrimazole greater than ketoconazole greater than RS 49910. We then examined the functional response of this binding by measuring tyrosine aminotransferase (TAT) activity in HTC cells. The antimycotics did not exhibit TAT agonist activity and inhibition of basal enzyme levels was not detected. However, the drugs were potent antagonists of dexamethasone-induced TAT activity and the effect was temporally reversible. This antagonist activity was in the same sequence and closely correlated with the binding potency of the three drugs. We conclude that ketoconazole and other imidazole antimycotic drugs possess glucocorticoid antagonist activity by virtue of occupancy of glucocorticoid receptor sites in target tissues.

Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes.

Ketoconazole has recently been shown to interfere with steroidogenesis in patients and rat in vitro systems. In this study we attempted to elucidate the site of inhibition in the adrenal gland. Although ketoconazole impaired adrenocorticotropic hormone stimulated cyclic (c)AMP production, dibutyrl cAMP addition did not bypass the steroidogenic blockade indicating that the critical ketoconazole-inhibited step was distal to cAMP. Addition of radiolabeled substrates to isolated adrenal cells and analysis of products by high performance liquid chromatography demonstrated a ketoconazole block between deoxycorticosterone (DOC) and corticosterone. This 11-hydroxylase step is carried out by a P450-dependent mitochondrial enzyme. No restriction of progesterone or pregnenolone conversion to DOC was detected, steps carried out by non-P450-dependent microsomal enzymes. Inhibition of cholesterol conversion to pregnenolone by mitochondrial fractions indicated a second block at the side chain cleavage step, another mitochondrial P450-dependent enzyme. Adrenal malate dehydrogenase, a non-P450-dependent mitochondrial enzyme was not inhibited while renal 24-hydroxylase, a P450-dependent mitochondrial enzyme in another organ, was blocked by ketoconazole. We conclude that ketoconazole may be a general inhibitor of mitochondrial P450 enzymes. This finding suggests that patients receiving ketoconazole be monitored for side effects relevant to P450 enzyme inhibition. Further, we raise the possibility that this drug action may be beneficially exploited in situations where inhibition of steroidogenesis is a therapeutic goal.

Quantitative tumor apoptosis imaging using technetium-99m-HYNIC annexin V single photon emission computed tomography.

PURPOSE: Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m- (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. PATIENTS AND METHODS: Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. RESULTS: Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P =.012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. CONCLUSION: In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.

Diagnosis and Treatment of Venous Malformations. Consensus Document of the International Union of Phlebology (IUP): updated 2013.

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects) . These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/ persistence rates, high morbidity following non-specific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular sub-types of VMs. This incorporated the embryological ongm, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustrated as a separate topic to differentiate from isolated VMs and to rectify the existing confusion with name-based eponyms such as Klippei-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndromebased VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Glucocorticoid receptors in adipose tissue.

Although adipose tissue appears to be a target organ for glucocorticoid hormones, previous studies have failed to detect glucocorticoid receptors in this tissue. In the present study, the addition of thioglycerol and trasylol to the homogenization medium provided an enuironment in which receptors were successfully demonstrated. [3H]Dexamethasone binding studies were carried out at 0 C in cytosol from various adipose tissues of adrenalectomized rats and bound hormone was separated from free by Sephadex chromtography. Despite the presence of protein protective agents, receptor binding decayed significantly over 24 h but appeared stable from 1 to 5 h. Epididymal fat pad cytosol had an apparent Kdiss at 0 C for dexamethasone of approximately 6 nM and a binding capacity of approximately 200 fmol per mg protein. To prove that the receptors were located in fat cells and not in surrounding connective tissue, isolated adipocytes were prepared by collagenase digestion and receptors were demonstrable in the cytosol from these cells as well. The affinity of series of steroids for the receptor was in the sequence: dexamethasone greater than corticosterone greater than progesterone greater than aldosterone greater than cortexolone greater than testosterone greater than estradiol. Receptors of roughly the same affinity but somewhat fewer binding sites on the basis of cytosol protein were also found on other fat depots including peri-renal, peri-scrotal and popliteal. Of interest is the fact that interscapular brown fat and human subcutaneous fat also possessed similar these receptors, the higher competitive capacity of dexamethasone indicated that the binding was to glucorticoid rather than mineralocorticoid receptors. The data suggest that fat cells contain glucocorticoid receptors which are similar to those seen in other glucocorticoid targets. Presumably these receptors mediate the effects of glucorticoids on adipose tissue.

Demonstration of glucocorticoid receptors in the adrenal cortex: evidence for a direct dexamethasone suppressive effect on the rat adrenal gland.

The adrenal cortex was evaluated for the presence of glucocorticoid receptors and functions. Substantial binding of [3H]dexamethasone was observed in aminoglutethimide-treated, hypophysectomized, and intact rats. Further studies demonstrated binding in cultured bovine adrenocortical cells and in Y-1 cells, a cloned murine cell line of adrenal cortical origin. Scatchard analysis of specific binding data in cytosol from hypophysectomized rats revealed an apparent Kd of approximately 15 nM and a receptor content (Nmax) of 123 fmol/mg cytosol protein. Analysis of Y-1 cell cytosol showed a Kd of approximately 17 nM and Nmax of 190 fmol/mg protein. The binding site in hypophysectomized rats had the following steroid specificities: high affinity for dexamethasone, corticosterone, and progesterone; moderate affinity for 11 beta-cortisol, and low affinity for testosterone, estradiol, pregnenolone, and 11 alpha-cortisol. Sedimentation in sucrose density gradients revealed 8S binding peaks in cytosols prepared from intact rat adrenal glands, Y-1 cells, and cultured bovine adrenocortical cells. Time- and temperature-dependent nuclear uptake of [3H]dexamethasone in Y-1 cells was demonstrated. In vivo treatment of hypophysectomized rats with dexamethasone significantly enhanced the rate of adrenal atrophy. ACTH stimulation tests in hypophysectomized rats showed a decreased corticosterone response in dexamethasone-treated rats compared to that in control animals. However, in vitro, there was no evidence for an effect of dexamethasone on ACTH-stimulated corticosterone production. The data indicate that the adrenal cortex possesses a high affinity binding site that fulfills the criteria for a glucocorticoid receptor. Glucocorticoid administration enhances adrenal atrophy and impairs adrenal function. We speculate that this action contributes to the suppressive effect of glucocorticoids on the pituitary-adrenal axis.

Rheological changes in the blood of patients with chronic arterial occlusive disease after the administration of vasoactive drugs.

Patients with chronic arterial occlusive disease were found to have higher blood and plasma viscosity levels than healthy controls. Measurements were taken at high and low shear rates. Blood and plasma viscosity in these patients was significantly reduced following parental administration of pentoxifyline, and this effect was particularly pronounced at low shear rates. The changes recorded after administriation of bencyclane did not follow a consistent pattern. There was no significant correlation between the rheological changes measured and changes in plasma protein fractions.

Combined treatment of congenital vascular defects: indications and tactics.

Congenital AV shunting defects are not as rare as sometimes presumed, and they are four times more frequent in girls than in boys. Inadequate treatment can aggravate the patient's complaints by increasing the circulatory disturbance in the affected region. As a result, ischemic ulceration may develop. Special, usually interdisciplinary, treatment of such findings is mandatory. When AV communications are present, the combined treatment of surgical and nonsurgical techniques must be considered. Location and pathoanatomic type influence this choice. Clinical, functional, and hemodynamic parameters must also be evaluated in order to decide the optimal combination of therapeutic measures. Usually several phases of treatment are necessary.

[An investigation into the problem of streaming in the femoral artery by means of high speed serial angiography and synchronous pulse recording (author's transl)]. / Untersuchungen zur Frage des Strömungsverhaltens in der Arteria femoralis mittels Schnellserienangiographie und synchroner Pulswellenregistrierung

A method is described which allows one to correlate pulsephase dependant streaming and movement of the vessel wall by means of synchronous registration of pulse volume curves and the appearance of streaming as shown by serial angiograms. The results of this investigation in the femoral artery confirm the accepted view that the appearance of streaming depends on the movements of the vessel wall. The prognostic value for vessel reconstruction is discussed.

Surgical treatment of congenital vascular defects.

The special nature of the anatomopathological structure and of the haemodynamic disturbances in congenital vascular defects causes certain peculiarities in their operative treatment. In our experience therapeutical strategy should be based on the following basic principles: active causal therapy combating pathogenesis, individual treatment, early operation, functionally radical operation, operation by stages and combined treatment. The numerous operative techniques are subdivided as follows according to surgical tactics: reconstructive operations, operations to remove the vascular defect, operations to reduce haemodynamic activity of the vascular defect and other nonhaemodynamic operations. Good postoperative results obtained after the use of the principles indicated above in a large number of patients treated by vascular surgeons in six different countries proved the validity of active and causal treatment of these severe diseases.

The surgical treatment of predominantly venous defects.

The predominantly venous defects consist of the truncular forms, as there is aplasia or obstruction in the truncular dilatation; and they consist of the extratruncular forms as there are the infiltrating ones and the limited ones, according to the Hamburg classification. The web or membranous obstruction of the inferior vena cava (IVC), dilatation or aneurysm of the jugular vein, infiltrating "cavernous angioma" and localized venous defects are the main lesions of those classifications reported in this communication. Jugular dilatation and localized extratruncular lesions have had good therapeutic results. Webs of the IVC can be treated by membranectomy, either by finger, transcardially, or balloon, percutaneously, and cavo- or mesoatrial shunt; however, membranectomy, along with cavoplasty as a radical treatment for such an entity, is advocated by the authors. The infiltrating extratruncular form is the unsolved important issue concerning its thorough resection. Skin graft taken from a resected tissue mass through a reversal split thickness skin graft by a drum type dermatome, removal of the lesion along with muscle layer(s), and staged operations are recommended.

Surgical treatment in predominantly arterial defects.

The predominantly arterial defects are not common. Four anatomical forms are distinguished: truncular aplasia or obstruction, truncular dilatation, extratruncular infiltrating form and extratruncular limited form. They are demonstrated through an analysis of 40 cases treated by the authors. The therapeutic principles for them are the same as those applying to standard vascular surgery. Regarding the infiltrating extratruncular lesion, an initial embolization through the afferent artery and a series staged operation are suggested.

[Venous aneurysms]. / Venöse Aneurysmen.

Incidence, etiology, diagnostic procedures and therapy of venous aneurysms, basing on 152 own cases, are discussed. The main procedure for diagnosis is phlebography. It must be distinguished between aneurysms of epi- and subfascial veins. The localization determines the surgical procedure which represents the only successful therapy. Without proper treatment, venous aneurysms may be responsible for complications such as thrombophlebitis, thrombosis with pulmonary embolism, aneurysm rupture and compression of adjacent structures. The results of surgical treatment are excellent.

Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. DAWID Study Group.

BACKGROUND: Intravenous iloprost, titrated from 0.5 up to 2.0 ng/kg/min has been shown in patients with PAOD III/IV to significantly improve healing of trophic lesions, relief of rest pain, and reduce the rate of major amputation or death at 6 months as compared to placebo. The effect is considered related to improvement of the microcirculation. The aim of the present trial was to identify an optimum dose regarding treatment response and tolerability, by studying 4 doses of 25, 50, 75 and 100 micrograms iloprost daily. PATIENTS AND METHODS: 302 patients with PAOD IV were randomised via a double-blind fashion to one of the 4 doses. The primary endpoint was the responder rate at end of treatment. Responders were defined as patients with very good or good global efficacy, as judged by lesion healing and pain relief. Side effects were documented and a pre-defined benefit/risk index was calculated. RESULTS: No dose-dependency of iloprost regarding primary or secondary endpoints was observed. The rate of responders ranged between 48.7-53.5%. Side effects, mainly related to vasodilation, increased dose-dependently (p < 0.001, chi 2-test), with a significant decrease of the benefit/risk index from 2.19 +/- 1.19 to 1.64 +/- 0.97 (p = 0.012, ANOVA). Responders had a better outcome at 6 months than non-responders (2.6 fold higher rate of major amputation or death; life table analysis). CONCLUSIONS: It is concluded that iloprost should be titrated to the optimum rather than maximum tolerated dose, since a higher incidence of side effects not associated with an increased treatment response was observed at higher doses.

Iatrogenic vascular lesions: tactical procedure and late follow-up studies.

The problems associated with postoperative iatrogenic vascular lesions in 13 patients are discussed. In general surgery, there is no particular procedure which entails an extremely high risk of iatrogenic vascular lesions. Depending on the kind of lesion, hemorrhage and ischemia are the most frequent symptoms. The IVL was recognized during the initial operation in only two cases. Interposition of autologous saphenous vein is the safest therapeutic procedure. End-to-end anastomosis and patches to enlarge the anastomosis can also be used. In venous lesions, we recommend the creation of a temporary AV-fistula. In one case a thigh amputation was necessary because of progressive venous gangrene; operation was performed five days after the lesion. Postoperatively, two cubital interpositions were occluded; but the patients did not suffer from circulatory problems. One female patient died following resection of a carotid aneurysm originating from a glomectomy. Good postoperative results were reported for the other patients.

[Problems in the therapy of central arterial ectasias and elongations in long-lasting arteriovenous fistulas]. / Zur Problematik der Therapie von zentralen Arterien-Ektasien und -Elongationen bei lange bestehenden AV-Fisteln

Acquired arteriovenous fistulas should be surgically cured as soon as possible after the diagnosis. In all the patients we treated, the arteriovenous fistula had existed for quite a long time, i.e. up to 26 years. These arteriovenous fistulas were surgically closed by the separation-method, the resection of the vessels and vascular reconstruction, or by the transvenous technique. - Arteriovenous fistulas, which have been in existence for quite a long time, result in cardiac dilatation, which can be cured after closure of the arteriovenous fistula. Furthermore, there can be pathologic changes of the vein and artery wall: chronic venous insufficiency and arterial ectasia can result. - After closure of the arteriovenous fistula our patients no longer complained of venous reflux disturbances. Even after closure of the arteriovenous fistula, an arterial ectasia is not reversible. The reasons for this are discussed. Symptoms, which occur after the closure of an arteriovenous fistula, which had existed for a long period and had produced a severe arterial ectasia, are looked upon as an autonomous disease. During the progress of this disease many complications can occur, even the rupture of the ectatic artery. The question is therefore discussed, whether it is justified to resect the ectatic arterial segment together with the arteriovenous fistula and to implant an alloplastic vascular graft in its place during the initial operation.

Guideline. Diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (iup): updated-2013.

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects). These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following nonspecific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular subtypes of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustratedas a separate topic to differentiate from isolated VMs and to rectify the existing confusion with namebased eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.