Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Melbourne Risk Factor Study (MERFS) Group

BACKGROUND AND PURPOSE: Given that hypertension is now relatively well controlled and use of antiplatelet agents has increased, our primary aims were to investigate the risk of intracerebral hemorrhage (ICH) associated with hypertension and use of antiplatelet agents. METHODS: In this city-wide case-control study, 370 consecutive cases of primary ICH, verified by CT or autopsy, were identified from one of 13 Melbourne hospitals. Ten subjects (or their next of kin) could not be located and 29 refused to participate, resulting in 331 eventual cases. Patients were aged between 18 and 80 years and had no prior stroke. Population-based control subjects were individually age- (+/- 5 years), sex-, and geographically matched to subject cases. A questionnaire administered to participants (or next of kin) elicited information about prior exposure to various potential risk factors. RESULTS: Hypertension approximately doubled the risk of ICH (odds ratio, 2.55; 95% confidence interval, 1.72 to 3.79). The use of aspirinlike drugs, in doses used for secondary prevention of ischemic stroke or cardiac disease, was not associated with an increased risk of ICH (odds ratio, 0.66; 95% confidence interval, 0.20 to 2.21). Factors associated with a reduced risk of ICH were a history of cardiovascular disease, arthritis, or high cholesterol level; being moderately overweight or using hormone replacement therapy; and drinking coffee. CONCLUSIONS: Hypertension was the most important risk factor for ICH but not as high as previously reported, nor was it higher than that reported for ischemic stroke. There was no evidence for any association between the use of aspirinlike drugs and ICH.     

Potential application of p53 as an intermediate biomarker in Barrett's esophagus

Diagnosis of the neoplastic progression in Barrett's esophagus using the histologic classification of dysplasia is frequently difficult. The tumor suppressor protein p53, when mutated, confers a promoter effect on cell growth. The purpose of this study was to evaluate the applicability of p53 as an intermediate biomarker of malignancy in Barrett's esophagus. Archival analysis of 100 biopsy specimens of Barrett's esophagus and 10 esophageal adenocarcinomas were compared with 35 chronic esophagitis biopsy specimens. Immunocytochemistry using an anti-p53 monoclonal antibody was performed and elevated immunoreactivity quantitated microscopically. Data were analyzed using a logistic regression model. Significant p53 immunoreactivity occurred as follows: chronic esophagitis (0%), Barrett's esophagus without dysplasia (10%), with low-grade dysplasia (60%), with high-grade dysplasia (100%), and adenocarcinoma (70%). All cases of Barrett's esophagus were significantly immunoreactive when compared with the chronic esophagitis cases (p = 0.001). There was an increase in p53 immunoreactivity as the histologic classification progressed toward adenocarcinoma (p = 0.001). Progression to high-grade dysplasia may be predicted based on p53 immunoreactivity. These findings suggest a role for p53 as an intermediate biomarker in Barrett's esophagus.     

Two different genes encode ferrochelatase in Arabidopsis: mapping, expression and subcellular targeting of the precursor proteins

Six adolescents, five males with prolactin-secreting pituitary macroadenomas and one female with idiopathic hyperprolactinaemia, are described. Their ages at presentation ranged from 13 years 7 months to 16 years 6 months. Presenting symptoms included headache, visual field defect, arrested growth and puberty. Only two cases had galactorrhoea. Every case had an elevated serum prolactin level. Three had surgery before the results of serum prolactin were to hand. Each patient was treated with bromocriptine. Bromocriptine suppressed serum prolactin level to normal in four cases, but in the girl with idiopathic hyperprolactinaemia, bromocriptine was not useful. In two boys, serum prolactin was not suppressed with bromocriptine therapy alone, and they were subsequently treated with cabergoline, surgery and irradiation. Nevertheless, in children and adolescents with prolactin-secreting pituitary adenoma, bromocriptine should be the first line of treatment.     

The chronocorrection of disorders in the blood coagulation rhythm with kurantil in patients with decompensated rheumatic heart defects

The circadian pattern of hemocoagulation was studied in patients with decompensated rheumatic heart disease (DRHD) concurrent with stages I-II circulatory failure (CF) during complex treatment or medical treatment with disaggregants. Biorhythmological studies demonstrated that in patients with DRHD and CF chronotherapy with curantyl had some advantages over the traditional therapy during complex drug therapy. In these patients, the chronopatterns of circadian rhythms of hemocoagulative parameters tended to normalize under the influence of curantyl chronotherapy, by diminishing the signs of external desynchronization. Advantages of chronotherapy over the traditional treatment found in patients with DRHD and stages I-II CF, as manifested by its clinical effect in shorter periods (on days 4-5) when small daily and course doses of the drug were used. Based on the biorhythmological studies of hemostatic parameters, a method of curantyl chronotherapy was developed for patients with DRHD and stages I-II CF, which may optimize the therapeutical process in patients with this abnormality.     

Loss of protein kinase C inhibition in the beta-T594M variant of the amiloride-sensitive Na+ channel

We previously reported the presence of a novel variant (beta-T594M) of the amiloride-sensitive Na+ channel (ASSC) in which the threonine residue at position 594 in the beta-subunit has been replaced by a methionine residue. Electrophysiological studies of the ASSC on Epstein-Barr virus (EBV)-transformed lymphocytes carrying this variant showed that the 8-(4-chlorophenylthio) adenosine 3':5'-cyclic monophosphate (8cpt-cAMP)-induced responses were enhanced when compared to wild-type EBV-transformed lymphocytes. Furthermore, in wild-type EBV-transformed cells, the 8cpt-cAMP-induced response was totally blocked by the phorbol ester, phorbol 12-myristate 13-acetate (PMA). This inhibitory effect of PMA was blocked by a protein kinase C inhibitor, chelerythrine. We now have identified individuals who are homozygous for this variant, and showed that PMA had no effect on the 8cpt-cAMP-induced responses in the EBV-transformed lymphocytes from such individuals. Cells heterozygous for this variant showed mixed responses to PMA, with the majority of cells partially inhibited by PMA. Our results demonstrate that an alteration in a single amino acid residue in the beta-subunit of the ASSC can lead to a total loss of inhibition to PMA, and establish the beta-subunit as having an important role in conferring a regulatory effect on the ASSC of lymphocytes.     

Ex vivo cytotoxic drug evaluation by DiSC assay to expedite identification of clinical targets: results with 8-chloro-cAMP

There is a pressing need to reduce the time and cost of developing new cytotoxic agents and to accurately identify clinically active agents at an early stage. In this study, the differential staining cytotoxicity (DiSC) assay was used to assess the efficacy of the novel antitumour cAMP analogue, 8-chloro-cAMP (8-Cl-cAMP) (and its metabolite 8-Cl-adenosine) against 107 fresh specimens of human neoplastic and normal cells. Diagnoses included chronic and acute leukaemias, myeloma, non-Hodgkin's lymphoma (NHL) and miscellaneous solid tumours. The aim was to identify targets for subsequent phase I, II and III trials. 8-Cl-cAMP was tested at 4-985 microM, along with standard chemotherapeutic drugs. 8-Cl-cAMP and its metabolite caused no morphologically observable cell differentiation but induced dose-dependent cytotoxicity. Compared with untreated patients, previously treated chronic lymphocytic leukaemia (CLL) patients showed no increase in ex vivo resistance to 8-Cl-cAMP (P = 0.878); minimal cross-resistance with other cytotoxic drugs was detected. Compared with normal cells (mean LC90 = 1803 microM), 8-Cl-cAMP showed significant ex vivo activity against CLL (117.0 microM; P < 0.0001) and NHL (140.0 microM; P < 0.0001), of which eight were mantle cell NHL (84.7 microM), and greatest activity against cells from patients with acute myeloid leukaemia (AML; mean LC90 = 24.3 microM; in vitro therapeutic index 74-fold, P < 0.0001). Solid tumour specimens were comparatively resistant to 8-Cl-cAMP. The results highlight the clinical potential of 8-Cl-cAMP, point to several new phase I, II and III trial possibilities and provide a rationale for the inclusion of ex vivo cytotoxic drug evaluation in the drug development process.