Synergistic inhibition of thrombin-induced platelet aggregation by the novel nitric oxide-donor GEA 3175 and adenosine

1. The influence of the novel nitric oxide-donor GEA 3175 on thrombin- and ionomycin-stimulated human platelets was investigated. The effect of GEA 3175 was compared with that of adenosine, an activator of platelet adenylyl cyclase. 2. GEA 3175 inhibited thrombin-induced secretion of ATP but did not affect aggregation; similar results were obtained with adenosine. 3. Thrombin-stimulated rises in the cytosolic free Ca2+ concentration, [Ca2+]i, were dose-dependently inhibited by GEA 3175 and adenosine. GEA 3175 and adenosine maximally reduced the initial rise in [Ca2+]i by 41% and 35%, respectively. 4. Simultaneous exposure to GEA 3175 and adenosine nearly abolished both the functional responses (i.e. aggregation and degranulation) and the rises in [Ca2+]i in thrombin-stimulated platelets. 5. Aggregation and increases in [Ca2+]i triggered in platelets by the Ca(2+)-ionophore ionomycin were only marginally affected by a combination of GEA 3175 and adenosine. 6. GEA 3175 potently increased the guanosine 3':5'-cyclic monophosphate (cyclic GMP) content in platelets but did not affect adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. Adenosine did not increase either the cyclic AMP or the cyclic GMP levels in platelets. However, adenosine and GEA 3175 combined significantly elevated the platelet cyclic AMP content. 7. The results show that simultaneous exposure to GEA 3175 and adenosine promotes potent anti-aggregatory properties in platelets in vitro. The findings suggest that blockage of the cytosolic Ca(2+)-signal, which is probably mediated by an amplified cyclic nucleotide response, is an important event during the synergistic inhibition of thrombin-induced aggregation.     

Possibilities and limits of ambulatory supportive measures in oncology exemplified by antibiotic therapy of febrile neutropenia

Neutropenia is common after intensive chemotherapy. Hospitalization and intravenous broad-spectrum antibiotics are the standard of care for febrile neutropenic patients because of the risk of serious complications and associated mortality. Short neutropenic periods (< 7 days) are considered to be at a low-risk in cases when fever occurs in clinically stable patients. Recent work suggests that such a low-risk population of febrile neutropenic patients might benefit from alternatives to inpatient care. The agents that best qualify for outpatient treatment include quinolones i.v./p.o., glycopeptides, ceftriaxone and aminoglycosides, particularly if the latter are given once daily. Response rates to antimicrobial therapy range from 80 to 95% in low-risk febrile neutropenia episodes. Treating these patients in an outpatient setting avoids hospitalization in 75 to 95%. There is no doubt that outpatient therapy may have several advantages, including lower costs and an improved quality of live. Outpatient antibiotic therapy for febrile low-risk neutropenia should be considered as an acceptable alternative to inpatient treatment.     

A new use for an old Holter monitor: an ambulatory cough meter

Cough is commonly used as an outcome measure in clinical studies, although the subjective reporting of cough is unreliable when compared to objective measures. We describe an inexpensive new ambulatory cough meter that is based on a disused Holter monitor. The cough meter consists of a Holter monitor and a cough processor, designed on a computer to select the most appropriate filters. The cough meter was then validated against the overnight tape recorder on 21 occasions in 18 children (aged 6-15 yrs). The agreement between the cough meter and the tape recorder was good (mean difference of -0.3 coughs x h(-1); limits of agreement -2.2 to 1.7 coughs x h(-1)). We conclude that our newly described ambulatory cough meter provides a valid and inexpensive method of objectively monitoring cough for up to 24 h.     

Autacoid interactions in the regulation of blood flow in the human placenta

1. Interactions between autacoids may play important roles in the regulation of blood flow in the foetal placenta. In order to investigate this aspect of placental haemodynamics, human normal-term placentae were perfused in vitro and the responses of the foetal vessels to various combinations of vasoactive agents were determined. 2. Vasoconstriction responses to 5-hydroxytryptamine (5-HT) were potentiated in the presence of endothelin-1 (ET-1), the thromboxane A2-mimetic U46619 and a nitric oxide synthase inhibitor, N-nitro-L-arginine (NOLA), but not in the presence of angiotensin II. 3. N-Nitro-L-arginine caused vasoconstriction of the perfused placenta and indomethacin attenuated this effect and blocked the potentiation of the 5-HT response by NOLA. 4. Indomethacin did not affect ET-1-induced pressure increases and infusion of U46619 had no effect on release of ET-like immunoreactivity into the foetal placental circulation. 5. The present study provides evidence of interactions between several autacoids in human perfused placentae in vitro. These interactions may play important roles in foetal placental haemodynamics in normal or pathological situations.     

Class II major histocompatibility complex-deficient mice initially control an infection with Leishmania major but succumb to the disease

Class II major histocompatibility complex (MHC)-deficient (H-2b) mice do not express I-A or I-E molecules and, as a result, do not develop CD4 cells. Thus, they represent the ideal model for examining the importance of CD4 cells and MHC class II molecules in resistance to infection with Leishmania major and the capacity of MHC class I-restricted T cells to mediate resistance to L. major. Class II MHC-deficient mice and control (C57BL/6, normal and nude) mice were infected with L. major. Although MHC class II-deficient mice were able to control infection more effectively than nude mice, cutaneous lesions on the mice eventually progressed, and parasite replication became uncontrolled. These results suggest that CD4 cells and MHC class II molecules are essential for resistance to L. major and that in the absence of these cells and molecules, such mice can transiently control infection with L. major but are unable to resolve such infections.     

Sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of epidemiological surveillance data for 1970-96

OBJECTIVE: To identify changes in the occurrence of Creutzfeldt-Jakob disease that might be related to the epidemic of bovine spongiform encephalopathy. DESIGN: Epidemiological surveillance of the United Kingdom population for Creutzfeldt-Jakob disease based on (a) referral of suspected cases by neurologists, neuropathologists, and neurophysiologists and (b) death certificates. SETTING: England and Wales during 1970-84, and whole of the United Kingdom during 1985-96. SUBJECTS: All 662 patients identified as sporadic cases of Creutzfeldt-Jakob disease. MAIN OUTCOME MEASURES: Age distribution of patients, age specific time trends of disease, occupational exposure to cattle, potential exposure to causative agent of bovine spongiform encephalopathy. RESULTS: During 1970-96 there was an increase in the number of sporadic cases of Creutzfeldt-Jakob disease recorded yearly in England and Wales. The greatest increase was among people aged over 70. There was a statistically significant excess of cases among dairy farm workers and their spouses and among people at increased risk of contact with live cattle infected with bovine spongiform encephalopathy. During 1994-6 there were six deaths from sporadic Creutzfeldt-Jakob disease in the United Kingdom in patients aged under 30. CONCLUSIONS: The increase in the incidence of sporadic Creutzfeldt-Jakob disease and the high incidence in dairy farmers in the United Kingdom may be unrelated to bovine spongiform encephalopathy. The most striking change in the pattern of Creutzfeldt-Jakob disease in the United Kingdom after the epidemic of bovine spongiform encephalopathy is provided by the incidence in a group of exceptionally young patients with a consistent and unusual neuropathological profile. The outcome of mouse transmission studies and the future incidence of the disease in the United Kingdom and elsewhere, will be important in judging whether the agent causing bovine spongiform encephalopathy has infected humans.