FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

On the role of vasopressin and angiotensin in the development of irreversible haemorrhagic shock

1. Long-lasting haemorrhagic hypotension (4.5 hr at 35 mmHg) leading to irreversible haemorrhagic shock, has been studied in normal dogs, in dogs treated with a bradykinin potentiating nonapeptide (BPP(9a)), which blocks the conversion of angiotensin I to angiotensin II, and in dogs with experimental chronic diabetes insipidus (DI dogs). BPP(9a) was given by I.V. injection before the start of bleeding (BPP pre-treated group), 45 min after blood pressure had reached 35 mmHg (BPP early treated group) or 2 hr after blood pressure had reached 35 mmHg (BPP late-treated group). After retransfusion of blood all dogs were allowed to recover and observed for a further period of 3 days.2. Untreated control dogs developed haemorrhagic shock with tachycardia, low cardiac output, low total peripheral conductance and low stroke volume. All died within 24 hr of retransfusion, with pathological lesions typical of irreversible haemorrhagic shock.3. BPP pre-treated dogs developed haemorrhagic shock with bradycardia (during early shock), high cardiac output, high peripheral vascular conductance and high stroke volume when compared with the untreated controls. All pre-treated animals survived the 3 day observation period. They were then killed and on post-mortem showed no signs of irreversible haemorrhagic shock.4. BPP early-treated animals behaved like controls before BPP, but like pre-treated animals after the drug. Only one out of eight died within the 3 day observation period.5. BPP late-treated dogs behaved like controls before BPP. They responded to the drug with a rise in cardiac output, peripheral vascular conductance and stroke volume, and with a fall in heart rate. These responses were, however, short-lived. Four out of these eight animals died within the 3 day observation period, with lesions of irreversible haemorrhagic shock.6. DI dogs developed haemorrhagic shock with tachycardia (like controls), but with high cardiac output and peripheral vascular conductance (like BPP pre-treated dogs). The stroke volume of DI dogs was intermediate between those of controls and pre-treated groups. All six dogs survived the 3 day observation period.7. BPP(9a) had no measurable effect on the course of endotoxic shock.8. It is suggested that the normally severe vasoconstriction of the mesenteric vascular bed, which is thought to be responsible for irreversible haemorrhagic shock, is absent or attenuated in the absence of vasopressin or angiotensin. The consequences of this on the development of irreversibility are discussed.     

AIDS awareness in the conduct of radiologic procedures: guidelines to safe practice

The epidemic of the acquired immunodeficiency syndrome (AIDS) has affected all geographic regions of the United States. Indeed, it is likely that a majority of U.S. hospitals have cared for patients who are infected with the human immunodeficiency virus (HIV), the virus that causes AIDS. More than 46,000 individuals with HIV infection have fulfilled the strict diagnostic criteria for AIDS (1). All of these patients with AIDS have been seriously ill and have been hospitalized, often multiple times and for prolonged periods. Another, larger group patients with HIV infection has had another form of the disease, the so-called AIDS-related complex. Many of these patients have also spent time in hospitals. An even larger group of individuals has been infected with HIV but has remained asymptomatic to date. Some of these persons have been admitted to hospitals or have received outpatient diagnostic procedures for intercurrent medical or dental complaints that were unrelated to their asymptomatic HIV infection. At the time of their medical evaluation, some of these asymptomatic individuals were known to have a positive HIV antibody test. It is likely, however, that the serologic status of the majority of asymptomatically infected patients was unknown. Thus, by now a very large number of health-care personnel in the United States, including diagnostic radiology staff, have assisted in the care of HIV-infected patients.     

PURIFICATION AND CHARACTERIZATION OF A VARIANT OF HUMAN PROTHROMBIN: PROTHROMBIN SEGOVIA

A dysprothrombin designated prothrombin Segovia was isolated from the plasma of an individual with normal prothrombin antigen and prothrombin activity lesser than 25% of the control prothrombin activity. Activation by prothrombinase complex showed a lower amidolytic than clotting activity, which suggests a lesser generation of active intermediates than normal prothrombin. When prothrombin Segovia was activated by prothrombinase complex in the absence of factor Va, no thrombin formation was found by functional activities. SDS-PAGE analysis of the molecules derived by activation with prothrombinase complex, Taipan snake venom and Echis carinatus venom showed an accumulation of molecules not cleaved at bond Arg320-Ile321. This was more evident with Echis carinatus venom, which only acts on this bond. Our data suggest that the alteration of prothrombin Segovia impairs the scission of bond Arg320-Ile321. © 1997 Elsevier Science Ltd     

Baroreceptor regulation of salt intake

Baroreceptor input plays a critical role in body fluid balance and the endocrine response to NaCl consumption [25]. Experiments were performed to characterize the alterations in salt intake that are seen after baroreceptor denervation. Using chronically baroreceptor denervated (SAD) or control (CON) male Sprague-Dawley rats, we determined: 1) concentration-dependent consumption of NaCl, 2) time course of saline intake, 3) effect of food access on saline intake, 4) intake of sucrose vs. saline, and 5) water vs. saline intake using a choice paradigm. In protocols 1–4 the rats were given a single bottle containing saline or sucrose for a 2-h period during the early dark period. A comparison of the intake of varying concentrations of NaCl (0.3 to 2.0% NaCl, six concentrations) demonstrated that the SAD consumed significantly less NaCl than the CON (from 0.9 to 2% NaCl), Saline intake in SAD was 14–56% of the CON (significant group, salt concentration and interaction effects). Regression analysis demonstrated that in the SAD there was an inverse relationship between concentration and the amount of NaCl consumed (p < 0.02), an effect not seen in the CON. There were also differences in the pattern of saline intake with the CON showing the highest consumption in the early dark period with a gradual decrease as compared to the SAD, which demonstrated a uniformly lower pattern of consumption. The reduction in intake in the SAD appeared to be specific for NaCl because there was no difference in water or sucrose intake. The deficit could not be attributed to alterations in food intake, nor was there any difference in the amount of water consumed after the saline challenge.