Norepinephrine and serotonin: Specificity of release with rewarding electrical stimulation of the brain

Using a push-pull cannula method the amygdala of rats was perfused to examine the release of labeled norepinephrine (NE) and labeled serotonin (5-HT) during electrical stimulation of the brain (ESB) determined by prior behavioral testing to be rewarding or non-rewarding. Simple sensory stimulation was used during perfusion to examine further the degree of specificity of release of these amines. Highly rewarding ESB, but not the sensory stimulation, was accompanied by release of both NE and 5-HT. Varying current intensity had significant effects on the amount of these amines released. Furthermore, non-rewarding ESB was accompanied by inhibition of release of NE and 5-HT and a control substance, urea, was not significantly released during rewarding ESB. The results were discussed as implicating both noradrenergic and serotonergic mechanisms in the mediation of reinforcement.     

Survivin splice variants regulate the balance between proliferation and cell death

Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DeltaEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.     

Pramipexole and levodopa in early Parkinson's disease: dynamic changes in cost effectiveness

BACKGROUND AND OBJECTIVE: In chronic disease, treatment effects and costs accumulate over time; hence, the choice of time horizon in cost-effectiveness analysis can be particularly important. In this article we analyse the dynamic changes in cumulative costs, effects and incremental cost effectiveness of two competing drug strategies in patients with early Parkinson's disease (PD). METHODS: Three hundred and one subjects with PD were randomised to initial pramipexole or levodopa and followed every 3 months over a 4-year period. Healthcare resource use was recorded in patient diaries and valued using a variety of sources at year 2002 US dollar values. Health-related quality of life (HRQoL) was measured using the EuroQoL EQ-5D. The study was conducted from a US societal perspective. Missing data were imputed using a multivariate fixed-effects model. Additional quality adjusted life years (QALY) gained by using pramipexole compared with levodopa were estimated as the area between the normalised treatment HRQoL profiles. The QALYs and costs for each treatment arm were calculated for various study horizons.The incremental cost-effectiveness ratio (ICER) and the net monetary benefit (NB) [using 50,000 US dollars, 100,000 US dollars and 150,000 US dollars as the value of a QALY] were estimated, and were bootstrapped to calculate the standard errors. Cost-effectiveness acceptability curves (CEAC) were built to estimate the probability that pramipexole was cost effective given different societal values of QALY, for various study horizons.We conducted sensitivity analyses on the ICER and the NB to test their robustness to various assumptions about missing data, for various subpopulations and under changes in the drug prices. RESULTS: Under the base-case assumptions, the ICER for pramipexole was 42,989 US dollars per QALY. Using the CEAC approach, the probability that pramipexole was cost effective relative to levodopa over the first 4 years was 0.57, 0.77 and 0.82 when a QALY was valued at 50,000 US dollars, 100,000 US dollars, and 150,000 US dollars, respectively. Over time, the ICER for pramipexole improved and uncertainty around the ICER decreased. If, after treatment withdrawal, HRQoL improved in pramipexole subjects and declined in levodopa subjects (best-case scenario for pramipexole), the probability of pramipexole being cost effective increased to 0.88, 0.96 and 0.98, respectively. Factors that improved the ICER of pramipexole were a decrease in the relative price of pramipexole and having low HRQoL or depression at baseline. CONCLUSIONS: The cost effectiveness of pramipexole compared with levodopa in the treatment of early PD increased as the time horizon of the clinical trial extended from 2 to 4 years. Our results suggest that pramipexole is more cost effective for patients with depression and low baseline HRQoL than in other patient subgroups.     

Effect of intravenous contrast on treatment planning system dose calculations in the lung?

Intravenous contrast-enhanced computed tomography is utilised in radiotherapy lung treatment planning to improve the delineation of the tumour volume and nodal areas. In the resultant CT images, the electron density is increased within the vascular structures of the lung and the overall density in the lung volume may also be increased. As yet, it is unclear whether the change in density affects the accuracy of dose calculations based on this CT data. Two investigations were undertaken. Firstly, contrast-enhancement was simulated using an anthropomorphic phantom. In the second investigation, bulk density corrections were performed in an existing patient dataset. In both investigations, treatment plans were generated using both pre- and post-contrast datasets. The numbers of monitor units calculated in each of the plans were compared, as were the resulting isodose curves, dose volume histograms and physical mean lung doses. The numbers of monitor units calculated from the contrast- and non contrast-enhanced datasets agreed within 2%. The isodose curves and dose volume histograms showed very minor differences in size and shape. With the introduction of contrast agent, the physical mean lung doses calculated remained below the limit recommended for an acceptable plan. These results indicate that the introduction of contrast agent has a minimal dosimetric impact upon lung cancer treatment plans.     

Prognosis and decision making in severe stroke

Context  An increasing number of deaths following severe stroke are due to terminal extubations. Variation in withdrawal-of-care practices suggests the possibility of unnecessary prolongation of suffering or of unwanted deaths. Objectives  To review the available evidence on prognosis in mechanically ventilated stroke patients and to provide an overall framework to optimize decision making for clinicians, patients, and families. Data Sources  Search of MEDLINE from 1980 through March 2005 for English-language articles addressing prognosis in mechanically ventilated stroke patients. From 689 articles identified, we selected 17 for further review. We also identified factors that influence, and decision-making biases that may result, in overuse or underuse of life-sustaining therapies, with a particular emphasis on mechanical ventilation. Evidence Synthesis  Overall mortality among mechanically ventilated stroke patients is high, with a 30-day death rate approximating 58% (range in literature, 46%-75%). Although data are limited, among survivors as many as one third may have no or only slight disability, yet many others have severe disability. One can further refine prognosis according to knowledge of stroke syndromes, early patient characteristics, use of clinical prediction rules, and the need for continuing interventions. Factors influencing preferences for life-sustaining treatments include the severity and pattern of future clinical deficits, the probability of these deficits, and the burdens of treatments. Decision-making biases that may affect withdrawal-of-treatment decisions include erroneous prognostic estimates, inappropriate methods of communicating evidence, misunderstanding patient values and expectations, and failing to appreciate the extent to which patients can physically and psychologically adapt. Conclusions  Although prognosis among mechanically ventilated stroke patients is generally poor, a minority do survive without severe disability. Prognosis can be assessed according to clinical presentation and patient characteristics. There is an urgent need to better understand the marked variation in the care of these patients and to reliably measure and improve the patient-centeredness of such decisions.      

Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function

RATIONALE: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. OBJECTIVES: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. METHODS: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. MAIN RESULTS: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. CONCLUSIONS: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.     

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.