The impact of generic substitution on the activities of pharmaceutical companies - a survey from the companies' perspective one year and five years after the introduction of generic substitution in finland

Background  

Mandatory generic substitution (GS) was introduced in Finland on 1 April 2003. The aim of this study was to explore and compare the impacts of GS on the activities of pharmaceutical companies representing mainly original or generic pharmaceutical products in Finland. The self-reported impact of GS from pharmaceutical companies' perspective was explored with a focus on the number of employees, the range of sales packages on the market, the marketing activities, the research and development of new pharmaceutical products and storage of pharmaceuticals.     

The Potential Role of Stream Habitat Restoration in Facilitating Salmonid Invasions: A Habitat‐Hydraulic Modeling Approach

Many successful invasions have taken place in systems where harmful disturbance has changed habitat conditions. However, less attention has been paid to the role of habitat restoration, which modifies habitats and thus also has the potential to facilitate invasions. We examined whether in‐stream habitat restorations have the potential to either facilitate or resist invasion by two widely introduced non‐native stream salmonids, Salvelinus fontinalis Mitchill and Oncorhynchus mykiss Walbaum, in Finland. A physical habitat simulation system was used to calculate whether the habitat area for the target species increased or decreased following the restorations. For comparison, we also reported results for four native stream fish species. The simulations showed that the restored streams provided the highest amount of usable habitat area for the native species, particularly for Salmo salar L. and Gottus gobio L. However, it was interesting to note that the restorations significantly increased habitat quality for the two non‐native species, especially at low flows. Nevertheless, the non‐native species had the lowest amount of usable habitat area overall. The modeling results indicated that not only habitat destruction but also habitat restoration could contribute to the spread of non‐native species. Fisheries and wildlife managers should be aware of the possibility, when restoring habitats in order to preserve native ecosystems, that non‐native species could manage to gain a foothold in restored habitats and use them as population sources for further spread. Knowing the widespread negative effect of non‐native species, this risk should not be underestimated.     

Identification of a novel streptococcal gene cassette mediating SOS mutagenesis in Streptococcus uberis

Streptococci have been considered to lack the classical SOS response, defined by increased mutation after UV exposure and regulation by LexA. Here we report the identification of a potential self-regulated SOS mutagenesis gene cassette in the Streptococcaceae family. Exposure to UV light was found to increase mutations to antibiotic resistance in Streptococcus uberis cultures. The mutational spectra revealed mainly G:C-->A:T transitions, and Northern analyses demonstrated increased expression of a Y-family DNA polymerase resembling UmuC under DNA-damaging conditions. In the absence of the Y-family polymerase, S. uberis cells were sensitive to UV light and to mitomycin C. Furthermore, the UV-induced mutagenesis was almost completely abolished in cells deficient in the Y-family polymerase. The gene encoding the Y-family polymerase was localized in a four-gene operon including two hypothetical genes and a gene encoding a HdiR homolog. Electrophoretic mobility shift assays demonstrated that S. uberis HdiR binds specifically to an inverted repeat sequence in the promoter region of the four-gene operon. Database searches revealed conservation of the gene cassette in several Streptococcus species, including at least one genome each of Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus mitis, Streptococcus sanguinis, and Streptococcus thermophilus strains. In addition, the umuC operon was localized in several mobile DNA elements of Streptococcus and Lactococcus species. We conclude that the hdiR-umuC-ORF3-ORF4 operon represents a novel gene cassette capable of mediating SOS mutagenesis among members of the Streptococcaceae.     

Cervical cancer screening programme in Finland with an example on implementing alternative screening methods

In Finland (population 5 million) the organised Pap screening programme for preventing cervical cancer has been in action already for 45 years. Women aged 30 to 64 are targeted (N 1.25 million) and the screening interval is five years. The programme invites women seven times in a lifetime; the attendance rate per one screening invitational round is 73%. The programme has affected markedly the cervical cancer rates in our country. During the decennia of its action there has been about 80% decrease in the age-adjusted cervical cancer incidence and mortality rates. The current age-standardised incidence rate is 4 and mortality rate 1 per 100,000 woman-years. In the current article we describe the organisational aspects of the programme; and pay attention to renovation of the programme taken place during the last decade when novel technological alternatives have been started to be used as the screening tests. By expanding the coverage and compliance of screening we still expect to increase the impact of the programme. Same time, efforts are needed to avoid overuse of services due to spontaneous screening, in order to decrease potential adverse effects and improve overall cost-effectiveness. A large-scale public health policy trial on Human papillomavirus (HPV) screening is on-going. Cross-sectional information available thus far suggests promising results. Follow-up of cancer rates after screening episodes are still required to evaluate optimal screening policies (e.g., screening intervals by age groups, and starting and stopping ages). We propose speeding up the use of modern technological alternatives in organised screening programmes.     

Can genetically based clines in plant defence explain greater herbivory at higher latitudes?

Greater plant defence is predicted to evolve at lower latitudes in response to increased herbivore pressure. However, recent studies question the generality of this pattern. In this study, we tested for genetically based latitudinal clines in resistance to herbivores and underlying defence traits of Oenothera biennis. We grew plants from 137 populations from across the entire native range of O. biennis. Populations from lower latitudes showed greater resistance to multiple specialist and generalist herbivores. These patterns were associated with an increase in total phenolics at lower latitudes. A significant proportion of the phenolics were driven by the concentrations of two major ellagitannins, which exhibited opposing latitudinal clines. Our analyses suggest that these findings are unlikely to be explained by local adaptation of herbivore populations or genetic variation in phenology. Rather greater herbivory at high latitudes can be explained by latitudinal clines in the evolution of plant defences.     

Cognitive functioning in opioid-dependent patients treated with buprenorphine,methadone, and other psychoactive medications: stability and correlates

Background

In many but not in all neuropsychological studies buprenorphine-treated opioid-dependent patients have shown fewer cognitive deficits than patients treated with methadone. In order to examine if hypothesized cognitive advantage of buprenorphine in relation to methadone is seen in clinical patients we did a neuropsychological follow-up study in unselected sample of buprenorphine- vs. methadone-treated patients.

Methods

In part I of the study fourteen buprenorphine-treated and 12 methadone-treated patients were tested by cognitive tests within two months (T1), 6-9 months (T2), and 12 - 17 months (T3) from the start of opioid substitution treatment. Fourteen healthy controls were examined at similar intervals. Benzodiazepine and other psychoactive comedications were common among the patients. Test results were analyzed with repeated measures analysis of variance and planned contrasts. In part II of the study the patient sample was extended to include 36 patients at T2 and T3. Correlations between cognitive functioning and medication, substance abuse, or demographic variables were then analyzed.

Results

In part I methadone patients were inferior to healthy controls tests in all tests measuring attention, working memory, or verbal memory. Buprenorphine patients were inferior to healthy controls in the first working memory task, the Paced Auditory Serial Addition Task and verbal memory. In the second working memory task, the Letter-Number Sequencing, their performance improved between T2 and T3. In part II only group membership (buprenorphine vs. methadone) correlated significantly with attention performance and improvement in the Letter-Number Sequencing. High frequency of substance abuse in the past month was associated with poor performance in the Letter-Number Sequencing.

Conclusions

The results underline the differences between non-randomized and randomized studies comparing cognitive performance in opioid substitution treated patients (fewer deficits in buprenorphine patients vs. no difference between buprenorphine and methadone patients, respectively). Possible reasons for this are discussed.

     

A high recombination rate in eusocial Hymenoptera: evidence from the common wasp Vespula vulgaris

Background

Longevity expressed as the number of days between birth and death is a trait of great importance for both human and animal populations. In our analysis we use dairy cattle to demonstrate how the association of Single Nucleotide Polymorphisms (SNPs) located within selected genes with longevity can be modeled. Such an approach can be extended to any genotyped population with time to endpoint information available. Our study is focused on selected genes in order to answer the question whether genes, known to be involved into the physiological determination of milk production, also influence individual's survival.

Results

Generally, the highest risk differences among animals with different genotypes are observed for polymorphisms located within the leptin gene. The polymorphism with a highest effect on functional longevity is LEP-R25C, for which the relative risk of culling for cows with genotype CC is 3.14 times higher than for the heterozygous animals. Apart from LEP-R25C, also FF homozygotes at the LEP-Y7F substitution attribute 3.64 times higher risk of culling than the YY homozygotes and VV homozygotes at LEP-A80V have 1.83 times higher risk of culling than AA homozygotes. Differences in risks between genotypes of polymorphisms within the other genes (the butyrophilin subfamily 1 member A1 gene, BTN1A1; the acyl-CoA:diacylglycerol acyltransferase 1 gene, DGAT1; the leptin receptor gene, LEPR; the ATP-binding cassette sub-family G member 2, ABCG2) are much smaller.

Conclusions

Our results indicate association between LEP and longevity and are very well supported by results of other studies related to dairy cattle. In view of the growing importance of functional traits in dairy cattle, LEP polymorphisms should be considered as markers supporting selection decisions. Furthermore, since the relationship between both LEP polymorphism and its protein product with longevity in humans is well documented, with our result we were able to demonstrate that livestock with its detailed records of family structure, genetic, and environmental factors as well as extensive trait recording can be a good model organism for research aspects related to humans.     

Fine root foraging strategies in Norway spruce forests across a European climate gradient

Fine root acclimation to different environmental conditions is crucial for growth and sustainability of forest trees. Relatively small changes in fine root standing biomass (FRB), morphology or mycorrhizal symbiosis may result in a large change in forest carbon, nutrient and water cycles. We elucidated the changes in fine root traits and associated ectomycorrhizal (EcM) fungi in 12 Norway spruce stands across a climatic and N deposition gradient from subarctic‐boreal to temperate regions in Europe (68°N–48°N). We analysed the standing FRB and the ectomycorrhizal root tip biomass (EcMB, g m^?2) simultaneously with measurements of the EcM root morphological traits (e.g. mean root length, root tissue density (RTD), N% in EcM roots) and frequency of dominating EcM fungi in different stands in relation to climate, soil and site characteristics. Latitude and N deposition explained the greatest proportion of variation in fine root traits. EcMB per stand basal area (BA) increased exponentially with latitude: by about 12.7 kg m^?2 with an increase of 10° latitude from southern Germany to Estonia and southern Finland and by about 44.7 kg m^?2 with next latitudinal 10° from southern to northern Finland. Boreal Norway spruce forests had 4.5 to 11 times more EcM root tips per stand BA, and the tips were 2.1 times longer, with 1.5 times higher RTD and about 1/3 lower N concentration. There was 19% higher proportion of root tips colonized by long‐distance exploration type forming EcM fungi in the southern forests indicating importance of EcM symbiont foraging strategy in fine root nutrient acquisition. In the boreal zone, we predict ca. 50% decrease in EcMB per stand BA with an increase of 2 °C annual mean temperature. Different fine root foraging strategies in boreal and temperate forests highlight the importance of complex studies on respective regulatory mechanisms in changing climate.     

GTI: a novel algorithm for identifying outlier gene expression profiles from integrated microarray datasets

Background

Meta-analysis of gene expression microarray datasets presents significant challenges for statistical analysis. We developed and validated a new bioinformatic method for the identification of genes upregulated in subsets of samples of a given tumour type (‘outlier genes’), a hallmark of potential oncogenes.

Methodology

A new statistical method (the gene tissue index, GTI) was developed by modifying and adapting algorithms originally developed for statistical problems in economics. We compared the potential of the GTI to detect outlier genes in meta-datasets with four previously defined statistical methods, COPA, the OS statistic, the t-test and ORT, using simulated data. We demonstrated that the GTI performed equally well to existing methods in a single study simulation. Next, we evaluated the performance of the GTI in the analysis of combined Affymetrix gene expression data from several published studies covering 392 normal samples of tissue from the central nervous system, 74 astrocytomas, and 353 glioblastomas. According to the results, the GTI was better able than most of the previous methods to identify known oncogenic outlier genes. In addition, the GTI identified 29 novel outlier genes in glioblastomas, including TYMS and CDKN2A. The over-expression of these genes was validated in vivo by immunohistochemical staining data from clinical glioblastoma samples. Immunohistochemical data were available for 65% (19 of 29) of these genes, and 17 of these 19 genes (90%) showed a typical outlier staining pattern. Furthermore, raltitrexed, a specific inhibitor of TYMS used in the therapy of tumour types other than glioblastoma, also effectively blocked cell proliferation in glioblastoma cell lines, thus highlighting this outlier gene candidate as a potential therapeutic target.

Conclusions/Significance

Taken together, these results support the GTI as a novel approach to identify potential oncogene outliers and drug targets. The algorithm is implemented in an R package (Text S1).