Inhibition of aldosterone biosynthesis by atriopeptins in rat adrenal cells

The effect of synthetic atriopeptins on basal and stimulated aldosterone secretion was determined in isolated adrenal glomerulosa cells of the rat. Neither atriopeptin I (1-21) or III (1-24, i.e., the Phe-Arg-Tyr carboxy-terminal extension of atriopeptin I) altered basal aldosterone release. However, if the cells were prepared from adrenals of sodium-depleted rats, the basal aldosterone release was increased by 9-fold, compared with cells from normal rats. This elevated release was inhibited by 32% by atriopeptin I and atriopeptin III. Atriopeptin III was more potent than atriopeptin I. Angiotensin II and adrenocorticotropin stimulated the release of aldosterone in a concentration-related manner. Both atriopeptin I and atriopeptin III inhibited the stimulation by the peptides. Atriopeptin I inhibited angiotensin II- and adrenocorticotropin-induced aldosterone production by 50% at concentrations of 12 and 11 nM, respectively, and 0.5 and 0.2 nM, respectively, for atriopeptin III. Potassium-stimulated aldosterone production was also inhibited by atriopeptin I and atriopeptin III with 50% inhibition at concentrations of 10 and 0.4 nM, respectively. Shorter peptides (1-20, 1-19, and 3-19) were equipotent to atriopeptin I (1-21) as inhibitors of angiotensin II-induced steroidogenesis. To determine the site at which atriopeptins inhibit aldosterone synthesis, we used cyanoketone to inhibit 3 beta-hydroxy-dehydrogenase and dissociate the early and late pathways. Angiotensin II (2 nM) increased the synthesis of pregnenolone (early pathway), as well as the conversion of [3H]corticosterone to [3H]aldosterone (late pathway). Atriopeptin III inhibited basal pregnenolone synthesis by 36% and completely blocked angiotensin II-stimulated synthesis. The peptide similarly inhibited the late pathway.(ABSTRACT TRUNCATED AT 250 WORDS)     

High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

A comparison of keratinocyte cell sprays with and without fibrin glue

Fibrin glue is an excellent template for cellular migration and has been shown to be an effective delivery system for cultured autologous keratinocytes. We have investigated whether fibrin glue has any benefit on the percentage of epithelial cover when cultured autologous keratinocytes are sprayed onto a freshly debrided wound bed.Three pigs were used for this study. This provided a total of 18 full thickness, vertically orientated wounds, each 4cm in diameter and isolated in PTFE chambers to prevent re-epithelialisation from the wound margins. Eight wounds were sprayed with cultured autologous keratinocytes suspended in 2ml culture medium and eight wounds were sprayed with cultured autologous keratinocytes suspended in 1ml of the fibrin/aprotinin component of Tisseel fibrin glue (Baxter) mixed with 1ml of culture medium. In the latter group the thrombin component of the fibrin glue kit was applied to the wound bed immediately prior to grafting. The remaining two wounds were used as controls and sprayed with either culture medium or fibrin glue without cells. Epithelial cover was calculated in whole-wound biopsies at 3 weeks using image analysis, histology and immunohistochemistry.The cell suspension in fibrin glue appeared to spread more evenly over the wound surface, with no pooling in the inferior aspect of the wound. However, mean epithelial area at 3 weeks in the fibrin group was 1.6cm(2) per wound compared with 1.8cm(2) for the non-fibrin group, as measured by image analysis of digital photographs. There was no statistically significant difference between the two groups (P=0.802). This surprising result was confirmed by histological analysis of the wound biopsies, with a good correlation between histological and image analysis data (R=0.967). There was no observable difference in the quality of the epithelium on histological and immunohistological analysis of either group.     

Abdominal aortic aneurysm repair in the over eighties

Between January 1980 and September 1988, 34 octogenarians underwent aortic aneurysm repair. There were 26 men and eight women with a median age of 83 years (range 80-88 years). Twenty underwent 'emergency' repair after presenting with pain and/or collapse: 11 with a retroperitoneal rupture, three with an intraperitoneal rupture and six with an expanding aneurysm. The mortality rate for this group was 35 per cent. During the same period 14 patients had an elective repair and there were no deaths within 30 days. The mean hospital stay for the elective group was 14.2 days compared with 17.0 days for survivors in the emergency group. There was no significant difference in terms of risk factors between those who developed postoperative complications and those who did not. These mortality rates compare favourably with our overall mortality results for elective (4.6 per cent) and emergency (31 per cent) surgery. Those patients over 80 years of age with infrarenal abdominal aortic aneurysms should not be refused surgery on the basis of age alone; each patient should be judged individually.     

Ross River virus and Barmah Forest virus infections: a review of history, ecology, and predictive models, with implications for tropical northern Australia

The purpose of the present article is to present a review of the Ross River virus (RRV) and Barmah Forest virus (BFV) literature in relation to potential implications for future disease in tropical northern Australia. Ross River virus infection is the most common and most widespread arboviral disease in Australia, with an average of 4,800 national notifications annually. Of recent concern is the sudden rise in BFV infections; the 2005-2006 summer marked the largest BFV epidemic on record in Australia, with 1,895 notifications. Although not life-threatening, infection with either virus can cause arthritis, myalgia, and fatigue for 6 months or longer, resulting in substantial morbidity and economic impact. The geographic distribution of mosquito species and their seasonal activity is determined in large part by temperature and rainfall. Predictive models can be useful tools in providing early warning systems for epidemics of RRV and BFV infection. Various models have been developed to predict RRV outbreaks, but these appear to be mostly only regionally valid, being dependent on local ecological factors. Difficulties have arisen in developing useful models for the tropical northern parts of Australia, and to date no models have been developed for the Northern Territory. Only one model has been developed for predicting BFV infections using climate and tide variables. It is predicted that the exacerbation of current greenhouse conditions will result in longer periods of high mosquito activity in the tropical regions where RRV and BFV are already common. In addition, the endemic locations may expand further within temperate regions, and epidemics may become more frequent in those areas. Further development of predictive models should benefit public health planning by providing early warning systems of RRV and BFV infection outbreaks in different geographical locations.     

Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II

Background and Purpose

Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo.

Experimental Approach

Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments.

Key Results

Acute administration of sunitinib decreased left ventricular (LV) dP/dt_max. Acute administration of isoprenaline increased LVdP/dt_max dose-dependently, while LVdP/dt_max was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity.

Conclusions and Implications

Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction.Table of Links

Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.