Cutaneous involvement of disseminated adenovirus infection in an allogeneic stem cell transplant recipient.

Infection by human adenoviruses can lead to significant morbidity and mortality in immunocompromised hosts, such as allogeneic stem cell transplant (SCT) recipients, with limited effective treatment options. Specific cutaneous manifestations of disseminated adenovirus infection are not well described. We report a woman in her twenties who received an allogeneic T-cell-depleted peripheral blood SCT for the treatment of severe aplastic anaemia and, 5 months post-transplant, was hospitalized for severe systemic adenovirus infection with progressive involvement of the colon, liver and lungs. Despite therapy with intravenous cidofovir, oral brincidofovir and intravenous immunoglobulin, she had progression of adenoviraemia and dissemination of adenoviral disease. The patient developed a progressive rash characterized by keratotic papules that began on the palms and soles and spread to the entire body. Histopathological examination of skin biopsies of individual skin lesions from the palm and abdomen showed focal acantholytic dyskeratosis and keratinocytes with hyperchromatic nuclei. Several keratinocyte nuclei were immunoreactive for adenovirus. The patient was further treated with ribavirin and adenovirus-specific cytotoxic T lymphocytes but experienced multisystem progression of adenovirus infection culminating in death.

[Physiology and pathophysiology of the vascular endothelin system: clinical implications]. / Physiologie und Pathophysiologie des vaskulären Endothelinsystems: klinische Implikationen.

The endothelium-derived 21 amino acid peptide endothelin-1 is one of the most potent vasoconstrictors. Endothelin-1 exerts its effects upon a variety of vascular and non-vascular cells through a direct interaction with specific receptors. Beyond its vasoconstrictive action on vascular smooth muscle cells endothelin-1 has mitogenic and pro-inflammatory properties. The present review deals with current experimental and clinical evidence for the involvement of endothelin-1 in several cardiovascular disorders with inflammatory components. We further discuss the potential clinical relevance of the endothelin system and therapeutical perspectives of anti-endothelin strategies in the treatment of cardiovascular disease.

The effects of the selective serotonin reuptake-inhibitor fluvoxamine on body weight in Zucker rats are mediated by corticotropin-releasing hormone.

Brain serotonin plays a crucial role in the regulation of food intake and body weight homeostasis. Previous data suggest an interaction with corticotropin-releasing hormone (CRH). To further examine the interaction between these neurotransmitters, the selective serotonin reuptake-inhibitor (SSRI) fluvoxamine was given intraperitoneally in fa/fa Zucker rats with and without the CRH-receptor-antagonist alpha-helical CRH administered intracerebroventricularly (i.c.v.). The saline treated animals gained weight. Fluvoxamine led to a significant weight loss while not affecting food intake. Furthermore, insulin levels in this animal model were reduced following fluvoxamine administration. These effects were antagonized by alpha-helical CRH and are thus most likely mediated via CRH or CRH-like peptides.

Effect of a short-term dietary creatine supplementation on high-energy phosphates in the rat myocardium.

The aim of this study was to find out whether creatine (Cr) feeding affects total creatine (TCr), phosphocreatine (PCr), adenine nucleotide contents and beta-hydroxy-acyl-CoA-dehydrogenase (HAD) activity in myocardium as compared to red skeletal muscle. Ten adult Wistar rats received Cr (2.5% of diet weight) for 7 days. In Cr fed rats, PCr was increased (by approx. 20%) in cardiac and in soleus muscles with ATP elevated in myocardium and TCr and free Cr in soleus. In both muscles, Cr feeding enhanced HAD activity. It is concluded, that dietary Cr does increase cardiac muscle high energy phosphate reserves and its oxidative potential.

[Cellular mechanisms of endothelial endothelin synthesis]. / Zelluläre Mechanismen der endothelialen Endothelinsynthese.

Endothelin-1 is a vasoactive peptide produced by endothelial cells. Endothelin-1 exerts potent vasoconstrictory effects upon vascular smooth muscle cells, and it may play a role in the pathogenesis of several cardiovascular disorders such as atherosclerosis and ischemic conditions. Besides the investigation of its biological effects, knowledge about cellular mechanisms of the synthesis, signal transduction pathway(s) and receptor-mediated actions on target cells is mandatory for the development of pharmacological strategies in the treatment of cardiovascular disease. In this review cellular mechanisms of endothelial endothelin-1 synthesis and release are discussed.

[Physiology and pathophysiology of the endothelin system in cardiovascular diseases]. / Zur Physiologie und Pathophysiologie des Endothelin-Systems bei kardiovaskulären Erkrankungen.

The endothelins are a family of potent vasoconstrictors and mitogenic agents. Since the isolation of ET-1 in 1988 the worldwide scientific research interest has mushroomed, resulting in considerable knowledge about molecular biology, biochemistry and pharmacological actions of these peptides. A body of evidence has parallelly emerged pointing to their role in some physiological phenomena as well as in the pathophysiology of cardiovascular disease. The future therapeutic use of anti-endothelin strategies may offer clinical benefit in many of these conditions.

Hypothenar hammer syndrome successfully managed with intravenous prostaglandin E1 and heparin and with correction of the thrombogenic risk profile. A case report.

A fifty-one-year-old man presented with a history, symptoms, and clinical findings typical of a hypothenar hammer syndrome in his dominant hand. A thrombotic obstruction in the distal section of the ulnar artery with multiple downstream occlusions of proper digital arteries were documented angiographically. Coexistence of additional cardiovascular risk factors (smoking-induced polycythemia, obesity, hypercholesterolemia, and hypertension) was identified. Conservative management with intravenous heparin and prostaglandin E1 together with measures directed at controlling the additional risk factors (repeated venesection, immediate smoking cessation, and low-lipid diet) resulted in a striking clinical and angiographic improvement of the digital perfusion, without resort to interventional measures or thrombolysis.

Muscle metabolism during exercise in dogs after 8-week confinement.

NASA: Several indicators of muscle metabolism were measured in dogs during exercise following 8 weeks of confinement in cages. Muscle tissue samples were studied at rest and following exercise for adenine nucleotides, creatine phosphate, creatine, glycogen, pyruvate, and lactate. Results indicate that confinement results in less efficient metabolic responses to exercise, decreased muscle glycogen at rest, and changes in the equilibrium between ATP breakdown and resynthesis during exercise.^ieng

Glucose infusion into exercising dogs after confinement: rectal and active muscle temperatures.

BACKGROUND: Intravenous glucose infusion into ambulatory dogs results in attenuation of exercise-induced increase of both rectal and thigh muscle temperatures. HYPOTHESIS: That glucose (Glu) infusion attenuates excessive increase in body temperature from restricted activity during confinement deconditioning. METHODS: Rectal (Tre) and quadriceps femoris muscle (Tmu) temperatures, metabolic rate, and blood samples were taken before and after 90 min of moderate treadmill exercise (mean = 3.1 +/- SE 0.2 W.kg-1) at Tdb = 21 +/- 1 degrees C and 45-60% rh from 7 male mongrel dogs (19.6 +/- SD 3.0 kg) with i.v. infusion of 40% Glu in 0.9% NaCl (0.07 ml.kg-1.min-1) or 0.9% NaCl (0.07 mg.g-1.min-1) both before and after 8 weeks of cage confinement. RESULTS: Mean (+/- SE) delta Tre (90-0 min) were: NaCl.after = 1.8 +/- 0.4 degrees C vs. 1.4 +/- 0.3 degrees C (NS) before confinement; Glu.after = 1.3 +/- 0.2 degrees C vs. 0.9 +/- 0.3 degrees C (p < 0.02) before confinement. Comparable delta Tmu (90-0 min) data were: NaCl.after = 2.5 +/- 0.4 degrees C vs. 1.9 +/- 0.4 degrees C (NS) before; Glu.after = 1.6 +/- 0.2 degrees C vs. 1.4 +/- 0.4 degrees C (NS) before. Glucose infusion significantly attenuated the rise of Tmu (1.9 degrees vs. 1.4 degrees C) only before confinement, but attenuated the rise of Tre both before (1.4 degrees vs. 0.9 degrees C) and after (1.8 degrees vs. 1.3 degrees C) confinement. Body temperature attenuation was not related to change in plasma volume, osmolality, [Glu], [lactate], [cortisol], or heat production with constant VO2. CONCLUSION: Intravenous glucose infusion attenuates the rise in exercise core temperature in deconditioned dogs by a yet undefined mechanism.

Low proteins C and S and activation of fibrinolysis in treated essential thrombocythemia.

The aim of this study was to investigate whether abnormalities in the fibrinolytic system and in the naturally occurring anticoagulant proteins could contribute to the thrombotic risk in essential thrombocythemia. Euglobulin lysis time, fibrin plate lysis area, tissue plasminogen activator antigen, and activity and plasminogen activator inhibitor antigen were measured before and after venous occlusion in a group of 16 patients with essential thrombocythemia and in 16 healthy age and sex matched controls. In addition, resting levels of antithrombin III, D-dimer, prothrombin fragment 1 + 2, and protein C and S were assessed. The results were related to the presence or absence of a thrombotic history. The results demonstrated that the patients had a significantly elevated fibrin plate lysis area and significantly decreased plasminogen activator antigen, both at baseline and after venous occlusion. They also had significantly decreased levels of plasma protein C and total protein S. There was a modest, non-significant elevation in the plasma concentration of D-Dimer and F 1 + 2. Those patients with a history of thrombosis had significantly lower protein C levels compared with individuals without a thrombotic history. We conclude that patients with essential thrombocythemia have evidence of activated fibrinolysis in the resting state and after stimulation. This, and the decreased levels of protein C and total protein S, may be secondary to chronic clinically occult thrombosis occurring in myeloproliferative disorders.

Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome.

BACKGROUND: Among patients with independent evidence of coronary disease and recent onset unstable angina or non-Q wave myocardial infarction the incidence of subsequent cardiovascular events is high. Markers predictive of adverse cardiac outcome in unstable angina and non-Q wave myocardial infarction need to be defined more accurately. Endothelin-1 is a potent endothelium derived vasoconstrictor peptide that may play a part in the pathophysiology of acute myocardial ischaemia. AIM AND STUDY DESIGN: In a study that specifically identified high risk patients a group of 16 consecutive patients with either unstable angina at rest or non-Q wave myocardial infarction were prospectively investigated to establish whether these conditions are associated with high plasma immunoreactive endothelin and whether endothelin concentration at presentation is related to cardiovascular events within the next 12 weeks. Controls consisted of a group of 40 healthy subjects. RESULTS: Patients had significantly higher mean (SD) plasma endothelin at presentation than did healthy controls (7.4 (1.1) v 5.0 (1.2) pg/ml, P < 0.0001). At nine weeks plasma endothelin was still significantly higher in those patients who had subsequent cardiovascular events, (n = 9, acute myocardial infarction or refractory angina with electrocardiographic changes and revascularisation procedures, 8.5 (2.6) pg/ml, P < 0.005 v controls) whereas its concentration returned to normal in those patients who had a favourable outcome (n = 7, 5.9 (0.7) pg/ml). Compared with those patients who had an uneventful course, patients with subsequent events had significantly higher plasma endothelin, both at presentation and at nine weeks (P < 0.05 on both occasions). IMPLICATIONS: Endothelin may contribute to the pathophysiology of acute coronary syndromes and may relate to subsequent cardiovascular outcome.

Tissue-type plasminogen activator and plasminogen activator inhibitor activities as predictors of adverse events in unstable angina.

Among patients with recent-onset unstable angina and evidence of ischemia or coronary artery disease, the incidence of subsequent cardiovascular events is high. The aim of this study was to investigate, in this high-risk population, whether unstable angina was associated with abnormalities of tissue-type plasminogen activator (t-PA) or plasminogen activator inhibitor (PAI) activities and whether, in a prospective study, any of these parameters would identify patients with an adverse cardiovascular prognosis. A group of 22 high-risk patients with unstable angina (64% event rate at 3 months) was studied prospectively for 12 weeks, and the fibrinolytic parameters measured at presentation were related to subsequent cardiovascular progress. A group of 20 age- and sex-matched healthy subjects acted as control subjects. Patients who had subsequent cardiovascular events (acute myocardial infarction or severe recurrent angina +/- intervention) had significantly elevated PAI activity at presentation compared with both those who remained event-free (p < 0.05) or with control subjects (p < 0.02). In addition, basal activation of fibrinolysis was demonstrated in unstable angina at presentation; this persisted at 9 weeks in patients with a favorable outcome (p < 0.02 vs control subjects), whereas it was no longer evident in those who developed cardiac events. These findings suggest that measurements of t-PA/PAI activity may reflect the underlying pathophysiologic state and relate to subsequent cardiovascular events in unstable angina.

Prospective evaluation of a prostacyclin-sparing aspirin formulation and heparin/warfarin in aspirin users with unstable angina or non-Q wave myocardial infarction at rest. The Antithrombotic Therapy in Acute Coronary Syndromes Research Group.

The aim of this trial was to compare the efficacy of combination antithrombotic therapy with a prostacyclin-sparing aspirin plus anticoagulation versus conventional aspirin plus anticoagulation, when added to antianginal therapy, in patients with unstable angina or non-Q wave myocardial infarction already being treated with aspirin. In a double-blind (for the aspirin) study, 144 prior aspirin users were randomized; 72 patients received controlled-release, prostacyclin-sparing aspirin 75 mg daily plus anticoagulation (intravenous heparin followed by warfarin to maintain the international normalized ratio at 2-3), and 72 patients received conventional aspirin 75 mg daily plus the same anticoagulation. Controlled-release aspirin was formulated to preserve endothelial cell prostacyclin synthesis. Trial therapy was begun by 13.2 +/- 12.3 h of qualifying pain, and continued for 12 weeks. The frequency of recurrent angina with electrocardiographic changes, myocardial infarction, or death, was analysed by intention to treat. At 12 weeks, events were: [table: see text] Twenty-six of the 42 (62%) recurrent ischaemic events occurred within 7 days of presentation. Four of the 144 patients (3%) experienced a major bleeding complication. It is concluded that in spite of maximal antithrombotic therapy, there is a significant failure rate of medical therapy in aspirin users presenting with unstable angina or non-Q wave myocardial infarction while at rest. Prostacyclin-sparing aspirin offers no clinical benefit over conventional aspirin.

Study of endothelial t-PA and vWf in normal subjects and in von Willebrand's disease.

Some well-described similarities exist between tissue plasminogen activator (t-PA) and von Willebrand factor (vWf) which may suggest a link in either the synthesis or release of both proteins from endothelial cells. To investigate this relationship further immunocytochemical localization of t-PA and vWf was performed in normal tissues and in skin obtained from patients with type I and type III von Willebrand's disease (vWd). Components of the fibrinolytic system were measured at baseline and after venous occlusion in healthy controls and patients with vWd. Patients with severe vWd received intravenous vWf concentrate, followed by desmopressin (DDAVP), to study the plasma response of vWf and t-PA. By immunocytochemical staining, t-PA was demonstrated in endothelial cells of normal skin, kidney and liver and also in the skin of patients with type I and type III vWd. vWf was localized in endothelial cells of all tissues except the specimens from an individual with severe vWd. Basal plasma levels of fibrinolytic components were normal in patients with vWd. Venous occlusion resulted in a rise of fibrinolytic activity in controls and patients with type I, but not type III, vWd. No rise in plasma t-PA was observed following DDAVP in severe vWd, even though near-normalization of plasma vWf levels had been obtained by prior infusion of vWf concentrate. It is concluded that the synthesis of t-PA and vWf is probably regulated by independent processes. Constitutive and regulated release of both proteins occur through different mechanisms and the basal secretion of t-PA is intact in severe vWd.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group.

BACKGROUND: The purpose of this study was to compare combination antithrombotic therapy with aspirin plus anticoagulation versus aspirin alone, when added to conventional antianginal therapy in patients with unstable rest angina or non-Q-wave myocardial infarction who were nonprior aspirin users. METHODS AND RESULTS: Two hundred fourteen patients were randomized; 109 were randomized to receive aspirin alone (162.5 mg daily) and 105 to receive a combination of aspirin plus anticoagulation, ie, aspirin 162.5 mg daily plus heparin (activated partial thromboplastin time, two times control) followed by aspirin 162.5 mg daily plus warfarin (international normalized ratio, 2 to 3). Trial therapy was begun by 9.5 +/- 8.8 hours of qualifying pain and was continued for 12 weeks. Primary end points were recurrent angina with ECG changes, myocardial infarction, and/or death. Analysis by intention to treat of primary events at 12 weeks was performed. At 14 days, there was a significant reduction in total ischemic events in the combination group versus aspirin alone (10.5% versus 27%, P = .004). An efficacy analysis of primary events at 12 weeks also revealed a large reduction in total ischemic events in the combination group versus aspirin alone (13% versus 25%, P = .06). Bleeding complications were slightly more common with combination therapy. CONCLUSIONS: In nonprior aspirin users, combination antithrombotic therapy with aspirin plus anticoagulation significantly reduces recurrent ischemic events in the early phase of unstable angina.

Prospective comparison of unstable angina versus non-Q wave myocardial infarction during antithrombotic therapy. Antithrombotic Therapy in Acute Coronary Syndromes Research Group.

OBJECTIVES: This study was designed to compare the response of unstable angina and non-Q wave myocardial infarction during treatment with antithrombotic therapy. BACKGROUND: Antithrombotic therapy is beneficial in patients with these two coronary syndromes. METHODS: In a multicenter trial of antithrombotic therapy in unstable angina or non-Q wave myocardial infarction, 358 patients admitted within 48 h of chest pain were randomized to antithrombotic therapy with either 1) aspirin alone, or 2) aspirin plus heparin followed by aspirin plus warfarin, and were prospectively followed up for 12 weeks. Admission cardiac enzyme analyses revealed unstable angina in 268 patients and non-Q wave myocardial infarction in 62. Given an event rate of about 25%, this study has a power of 80% to detect a 50% difference between the two groups. RESULTS: Patients with unstable angina and non-Q wave myocardial infarction were similar with regard to age, gender, coronary risk factors and prior antianginal medication. Primary end points at 12 weeks were recurrent ischemia, infarction and death. [table: see text] In the non-Q wave group, all infarctions and death occurred within the 1st week. CONCLUSIONS: Patients with unstable angina or non-Q wave myocardial infarction on antithrombotic therapy have a similar total number of ischemic events by 12 weeks. However, despite maximal medical therapy with antianginal and antithrombotic medication, patients with non-Q wave infarction have a significantly higher rate of reinfarction and death.

Hypohydration increases the plasma catecholamine response to moderate exercise in the dog (Canis)

1. The effects of hypohydration produced by 48 hr water deprivation were examined in dogs during moderate treadmill exercise at an ambient temperature (Ta) of 21 degrees C. 2. Hypohydration caused a significant elevation in plasma levels of adrenaline (A), proteins (pp) and osmolality (pOsm). 3. During 1 hr of running, plasma concentrations of adrenaline (A) and noradrenaline (NA) rose significantly, whilst no change in these hormones occurred in dogs hydrated ad libitum. 4. The results suggest that hypovolemia in the dog may be a sufficient stimulus to intensify the sympatho-adrenal response to moderate exercise performed at a room Ta.

Coagulation and fibrinolytic systems in type I diabetes: effects of venous occlusion and insulin-induced hypoglycaemia.

1. The effects of venous occlusion on the coagulation and fibrinolytic systems were investigated in six patients with type 1 (insulin-dependent) diabetes and 11 age- and sex-matched non-diabetic control subjects. The coagulation parameters (fibrinogen, prothrombin time, partial thromboplastin time with kaolin, von Willebrand factor antigen) did not differ between patients and control subjects either before or after 20 min of venous occlusion. No rise was observed in von Willebrand factor antigen after venous occlusion in either group. 2. In the diabetic patients, chronic activation of the fibrinolytic system was found at baseline, which was indicated by a shortened euglobulin lysis time (P < 0.01), increased tissue plasminogen activator activity (P < 0.05) and decreased plasminogen activator inhibitor type 1 antigen level (P < 0.05), when compared with control subjects. In both groups venous occlusion resulted in significant increments in all measurements, except plasminogen activator inhibitor type 1 antigen level. The post-occlusion values did not differ between the two groups, except the plasminogen activator inhibitor type 1 antigen level, which remained significantly lower in the diabetic patients. The mean increments in each parameter did not differ between the two groups. 3. Coagulation and fibrinolysis were assessed in response to acute insulin-induced hypoglycaemia. Von Willebrand factor antigen levels increased significantly in both groups, with no difference in maximal increments. Significant activation of the fibrinolytic system occurred in response to hypoglycaemia, demonstrated by shortened euglobulin lysis time and increased fibrin plate lysis, tissue plasminogen activator antigen level and tissue plasminogen activator activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The fibrinolytic system and proteins C and S in treated polycythaemia rubra vera.

This study was designed to assess whether factors other than high haemoglobin, thrombocytosis and abnormal platelet function predispose to thrombosis in polycythaemia rubra vera (PRV). Components of the fibrinolytic system and concentrations of the naturally occurring anticoagulants were measured in patients and controls in the resting state; the fibrinolytic capacity was reassessed after venous occlusion. The results were related to presence or absence of a history of thromboembolism. Under resting conditions, patients with PRV had reduced plasminogen activator inhibitor antigen levels and higher fibrin plate lysis area and tissue plasminogen activator activity. Protein C, protein S and factor V levels were reduced. Those patients with a history of thromboembolism had decreased tissue plasminogen activator activity after venous occlusion compared to those who had not experienced a thrombosis. We conclude that reduced fibrinolytic capacity may predispose to thrombosis in PRV. Despite treatment to normalize haemoglobin levels, the patients have persistent activation of their fibrinolytic systems. This, and reduced levels of proteins C and S, may be secondary to a chronic, clinically occult, disseminated intravascular coagulation.