Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas

Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.     

Area deprivation, social class, and quality of life among people aged 75 years and over in Britain

BACKGROUND: There is a shortage of research studies that assess how selected characteristics of neighbourhood and personal social circumstances contribute towards health-related quality of life (QoL) among older people. METHODS: Analysis of baseline data for 5581 people aged > or =75 years and over from the Trial of Assessment and Management of Older People in the Community. The scores for four dimensions from the UK version of the Sickness Impact Profile and for the Philadelphia Geriatric Morale Scale were analysed in relation to individual social class and the Carstairs score of socioeconomic deprivation for the enumeration district of residence. RESULTS: In age and sex adjusted analyses, the proportion of participants of social class IV/V living in the most deprived areas who were in the quintile with worst QoL scores was more than double that among those from social class I/II living in the least deprived areas. Individual social class and area deprivation score contributed roughly equally to this doubling for home management, self-care and social interaction, whereas social class appeared a stronger determinant for mobility. Adjustment for living circumstances, health symptoms, and health behaviours substantially reduced the excess risk associated with social class and area deprivation. Being in a rural area was associated with lower risk of poor morale. CONCLUSION: Poor socioeconomic characteristics of both the area and the individual are associated with worse functioning (QoL) of older people in the community. This is not fully explained by health status. Policy should consider community-level interventions as well as those directed at individuals.     

ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes

Genetic susceptibility modulates the impact of obesity on risk for type 2 diabetes. The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure. The three cohorts included 679 nonmigrant South Asians living in Chennai, India (223 with type 2 diabetes); 1,083 migrant South Asians living in Dallas, Texas (121 with type 2 diabetes); and 858 nonmigrant Caucasians living in Dallas, Texas (141 with type 2 diabetes). Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years. The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25% in the nondiabetic group and 34% in the diabetic group of South Asians living in Chennai (P = 0.01). The prevalence in the nondiabetic and diabetic groups were 33 and 45% (P = 0.01) for the South Asians living in Dallas and 26 and 39% (P = 0.003) for the Caucasians. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians.     

P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway

OBJECTIVE: Ceramide, an intermediate of apoptosis induction in response to chemotherapy, can be detoxified by glycosylation at the cytoplasmic surface of the Golgi membrane. P-glycoprotein (p-gp) might augment ceramide glycosylation by translocating glucosylceramide (GC) across the Golgi membrane. We aimed to show that glucosylceramide synthase (GCS) activity is linked to p-gp expression and resistance to ceramide-induced apoptosis in acute myeloid leukemia (AML). METHODS: Apoptosis and cell-cycle analysis were measured using propidium iodide staining and flow cytometry. Fluorescent microscopy assessed p-gp expression in, and rhodamine 123 uptake by, the Golgi. P-gp interaction with GC was assessed by modulation of rhodamine accumulation. The GCS activity assay was based upon the transfer of UDP-(3)H-glucose to C8-ceramide to form radiolabeled GC, by rate-limiting cell-derived GCS. TLC and fluorimetry were used to measure the metabolites of fluorescent ceramide. Cell viability was measured using 7-amino-actinomycin D staining and flow cytometry with an internal standard for cell enumeration. RESULTS: P-gp(+) cell lines (KG1a, TF-1) were resistant to C8-ceramide-induced apoptosis compared to p-gp(-) cell lines (HL-60, U937). P-gp inhibitors GF120918 and cyclosporin A enhanced ceramide-induced apoptosis in the p-gp expressing cells. P-gp expression was identified in the Golgi of these cells. Pgp's efflux function in TF-1 but not KG1a cells was inhibited by glucosylceramide. In the presence of p-gp inhibitors, R123 accumulation in the Golgi of TF-1 cells was lost, and GCS activity and lactosylceramide formation were downregulated. Intact cells were necessary for the involvement of p-gp in the regulation of GCS activity. CONCLUSION: Our data suggests that ceramide induces apoptosis in AML cells and that p-gp confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-1 cells.     

Susceptibility to infectious rash illness in pregnant women from diverse geographical regions

Varicella-zoster (VZV), rubella (RV) and parvovirus B19 (B19V) infections are important causes of rash illness in pregnancy, due to their potential adverse impact on both mother and fetus. We determined susceptibility to these infections in pregnant women attending our hospital in 2002. Age and nationality were recorded. Sera were tested for VZV, RV, and B19V antibody by enzyme immunoassay. Of 7,980 women screened for VZV IgG, 11.3% were seronegative and therefore susceptible to infection. Across different worldwide regions, 6.9% of Irish and other Western European women were susceptible to VZV, compared to 19.7% of other women tested (p < 0.001), most of whom were from Central and Eastern Europe, sub-Saharan Africa and Asia. Of 7,872 women screened for RV IgG, 2.3% were seronegative. Few Irish (0.6%) or other Western European women (0.7%) were rubella non-immune, but 5.5% of women from other regions tested were susceptible to rubella (p < 0.001). A random subset of 1,048 women were tested for B19V IgG. About 38% were susceptible, varying from 22% to 63% across the different regions studied. There are important differences in immunity to these infections and so of potential risk of an adverse outcome in indigenous and immigrant pregnant women in Ireland.     

Double-blind, randomized comparison of olanzapine versus fluphenazine in the long-term treatment of schizophrenia

This study was undertaken to evaluate the efficacy and safety of olanzapine compared with fluphenazine in the treatment of patients who met the Diagnostic and Statistical Manual, fourth edition (DSM-IV) diagnostic criteria for schizophrenia or schizoaffective disorder. This was a long-term (22-week), randomized, double-blind, parallel clinical trial. Sixty patients (mean age, 35.4 years) were randomly assigned to either olanzapine (n=30) or fluphenazine (n=30). They received treatment at three centers in Croatia during a 22-week study period and were assessed weekly for the first 6 weeks and monthly thereafter. Efficacy was measured using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Rating Scale (PANSS) and the Clinical Global Impression (CGI) Severity and Improvement scores. The Hillside Akathisia Scale (HAS), Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), vital signs, laboratory tests, and treatment-emergent adverse events were assessed to evaluate safety. The olanzapine group showed significantly greater mean decreases from baseline to endpoint for BPRS total (-25.8 vs. -16.5, P=.035), PANSS total (-45.7 vs. -29.5, P=.037), PANSS positive (-13.0 vs. -7.9, P=.034), and CGI Severity (-2.2 vs. -1.3, P=.031) scores. The olanzapine group showed greater mean decreases on all measures of extrapyramidal symptoms, significantly so for the SAS (-2.1 vs. 1.9, P=.004) and HAS (-3.4 vs. 2.6, P=.028). Patients in the fluphenazine group experienced a higher incidence of treatment-emergent adverse events (76.7% vs. 50.0%, P=.032). Weight gain was the most frequently reported adverse event in the olanzapine group (16.7% vs. 0.0%, P=.020). Akathisia (30.0% vs. 10.0%, P=.053) and insomnia (20.0% vs. 0.0%, P=.010) appeared most frequent in the fluphenazine group. Daily use of anticholinergics and benzodiazepines were both significantly greater for the fluphenazine group (P=.003 and.04, respectively). No significant changes were observed in vital signs, ECG, or clinical chemistry. The study indicates that olanzapine has advantages in both efficacy and safety compared to fluphenazine; however, the small sample size limits our ability to draw definitive conclusions.