Limited effects of preterm birth and the first enteral nutrition on cerebellum morphology and gene expression in piglets

Preterm pigs show many signs of immaturity that are characteristic of preterm infants. In preterm infants, the cerebellum grows particularly rapid and hypoplasia and cellular lesions are associated with motor dysfunction and cognitive deficits. We hypothesized that functional brain delays observed in preterm pigs would be paralleled by both structural and molecular differences in the cerebellum relative to term born piglets. Cerebella were collected from term (n=56) and preterm (90% gestation, n=112) pigs at 0, 5, and 26days after birth for stereological volume estimations, large-scale qPCR gene expression analyses (selected neurodevelopmental genes) and western blot protein expression analysis (Sonic Hedgehog pathway). Memory and learning was tested using a T-maze, documenting that preterm pigs showed delayed learning. Preterm pigs also showed reduced volume of both white and gray matter at all three ages but the proportion of white matter increased postnatally, relative to term pigs. Early initiation of enteral nutrition had limited structural or molecular effects. The Sonic Hedgehog pathway was unaffected by preterm birth. Few differences in expression of the selected genes were found, except consistently higher mRNA levels of Midkine, p75, and Neurotrophic factor 3 in the preterm cerebellum postnatally, probably reflecting an adaptive response to preterm birth. Pig cerebellar development appears more affected by postconceptional age than by environmental factors at birth or postnatally. Compensatory mechanisms following preterm birth may include faster white matter growth and increased expression of selected genes for neurotrophic factors and regulation of angiogenesis. While the pig cerebellum is immature in 90% gestation preterm pigs, it appears relatively mature and resilient toward environmental factor

Generic pregabalin : current situation and implications for health authorities, generics and biosimilars manufacturers in the future

The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain: its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, generics could be legally prescribed for any approved indication once one indication loses its patent. We aim to establish the current situation with pregabalin among principally European countries. Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact and collated into five tables. The scenarios ranged from extending the patent life of Lyrica (e.g. France), endorsing the prescribing of Lyrica for neuropathic pain (e.g. Catalonia and South Korea), and current prescribing of pregabablin for all indications (e.g. Serbia and Germany). Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed. The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication

Essential to increase the use of generics in Europe to maintain comprehensive health care?

INTRODUCTION: Reforms have been introduced across Europe to increase prescribing efficiency with existing drugs. These include measures to lower prices of generics as well as increase their prescribing versus originators and patented products in a class or related class. This is essential to maintain comprehensive health care in Europe given continued pressures. The alternative is insufficient funds for new innovative drugs and increasing drug volumes with ageing populations. OBJECTIVE: To review the influence of measures and initiatives to increase the prescribing and dispensing of generics at low prices on ambulatory care prescribing efficiency. In view of this, provide guidance as authorities strive to introduce further reforms to meet their goals. METHODOLOGY: A narrative review of published papers combined with case histories. RESULTS: The different supply- and demand-side measures have reduced generic prices to as low as 2% to 3% of pre-patent loss prices in some cases as well as appreciably enhanced their utilisation. As a result, prescribing efficiency has increased without compromising care. In some cases, the reforms have led to expenditure actually falling despite appreciably increased volumes. CONCLUSIONS: Increasing use of generics at low prices will help maintain the European ideals of comprehensive and equitable health care. However, countries will continually need to learn from each other

Variation in the prices of oncology medicines across Europe and the implications for the future

Introduction/ Objectives: There are increasing concerns among health authorities regarding the sustainability of healthcare systems with growing expenditure on medicines including new high-priced oncology medicines. Medicine prices among European countries may be adversely affected by their population size and economic power to negotiate. There are also concerns that prices of patented medicines do not change once the prices of medicines used for negotiations substantially change. This needs to be investigated as part of the implications of low-cost generic oncology medicines. Methodology: Analysing principally reimbursed prices of patented oral oncology medicines (imatinib, erlotinib and fludarabine) between 2013 and 2017 across Europe and exploring correlations between GDP, population size, and prices. Comparing the findings with previous research regarding prices of oral generic oncology medicines. Results: The prices of imatinib, erlotinib and fludarabine did vary among European countries but showed limited price erosion over time in the absence of generics. There appeared to be no correlation between population size and prices. However, higher prices were seen among countries with higher GDP per capita which is a concern for lower income countries referencing these. Discussion and Conclusion: It is likely that the limited price erosion for patented oncology medicines will change across Europe with increased scrutiny over their prices and value as more medicines used for pricing decisions lose their patents combined with growing pressures on the oncology drug budget. In addition, discussions will continue regarding fair pricing for new oncology medicines and other approaches given ever rising prices with research showing substantial price reductions for oral oncology medicines (up to -97.8% for imatinib) once generics become available. We are also seeing appreciable price reductions for biosimilars further increasing the likelihood of these developments

Functional and Ecological Aspects of the Mucus Trails of the Freshwater Gastropod Elimia potosiensis

This thesis qualifies functional and ecological aspects of mucus trails deposited by Elimia potosiensis collected from the Meramec River. Freshwater snails are most often recognized for their significant role in river and stream ecosystem function as primary consumers and prey items. However, their form of locomotion is the most energetically expensive found in the animal kingdom. Found in large numbers and densities, E. potosiensis is capable of coating large swaths of substratum with carbohydrate- and protein-rich mucus. This has the potential to affect ecosystem function at the most basal trophic level both energetically, by contributing nutrients and energy to the surrounding water body, and functionally, as a sticky substance to which microheterotrophs become adhered. In marine studies, researchers have found that bacteria can readily degrade gastropod mucus and that it can act as the basis for biofilm formation. There have also been studies that show unique employment of energy saving strategies by snails that use their trails to capture food items and to reduce production needs by following trails laid by conspecifics. Very little research has been conducted on freshwater gastropods. This study is the first to focus solely on the ecological and functional aspects of freshwater snail mucus. For this study, collections of E. potosiensis were made from a single site along the Meramec River to qualify the effect deposited mucus has on the adherence of microalgae and its potential for formation of biofilms. Overall, mucus-coated surfaces significantly more particles in flow than non-coated surfaces. The water velocity at which a trail is laid was not found to have an affect on the thickness, adhesive ability or persistence of a trail. However, the water velocity in which a trail is incubated in stream does have effect on the adherence rate of a trail. In this study, it was found that this was most likely due to the fact that trails in high water velocity come into contact with more particles during a given period of time due, in part, to its higher carrying capacity

Age of deformation episodes in the Palaeoproterozoic domain of northern Sweden, and evidence for a pre-1.9 Ga crustal layer

It is proposed in a companion paper that the volcanic rocks of the Skellefte Group in northern Sweden were deposited on a pre-1.9 Ga basement, rather than formed as a juvenile volcanic arc and subsequently accreted to the continent. It is suggested that the proposed basement, the Robertsfors Group to the south of Skellefteå, was already deformed during an early episode of deformation (D1), prior to the deposition of the Skellefte stratigraphic sequence during an extensional tectonic episode. A younger episode of deformation, D2, then affected both areas. This hypothesis has important implications for the evolution of the Svecofennian Province. To test it, by constraining the ages of the principal deformation episodes, we have undertaken both isotope dilution and ion microprobe studies of zircon and monazite from three localities in the Robertsfors Group. A phase of migmatisation directly related to D2 shear zones allows the dating of D2 at ≈ 1860 Ma. Other planar granitoid bodies, which cut the D1 structures, confirm the age of this event. In the context of earlier published data, we conclude that the correlation of D2 in the Robertsfors Group with the main folding in the Skellefte Group is valid. Another granitoid body, folded by D2 but emplaced after D1, contains a suite of zircons of apparent magmatic aspect, but with a spread of ages from 1870 to 1900 Ma. Because of the high MSWD, the suite was divided into two groups with ages of ≈ 1896 and 1874 Ma. Recognising the possibilities of inheritance and of updating by younger events, we have preferred to interpret the younger age as a minimum age for magmatic intrusion. This is consistent with the basement hypothesis but is our only definite constraint on the age of D1. However, we infer, using other evidence, that D1 is probably older than 1900 Ma. Xenocrysts, interpreted as detrital zircons derived from the associated metasediments, give ages between 2716 and 1941 ± 20 Ma. The latter age provides a maximum age of deposition for part of the Robertsfors Group and a maximum age for D1. Other sequences, to the south and west, considered broadly equivalent to the Robertsfors Group, are intruded by granitoids dated between ≈ 1920 and 1960 Ma, providing local minimum ages of deposition for the sequences involved. Regional correlation with respect to age and deformation style can be made with the pre-1.9 Ga Kalevian rocks to the NE, deposited on Archaean basement on the SW margin of the Karelian Province. We suggest that pre-1.9 Ga complexes, equivalent to the Robertsfors Group, are widespread in the Svecofennian Province, and were deposited in a marginal basin which may have been initiated as early as 2.2 Ga ago. This hypothesis of an extensive basement crustal layer evidently requires that a substantial volume of crustal growth occurred prior to 1.9 Ga, in contrast to previous hypotheses. Erosion of the pre-1.9 Ga basin rocks after D1 is also the likely source of the 2.1-1.9 Ga detrital zircons in younger sediments associated with the overlying post-1.9 Ga volcanics. The source of these detrital zircons has previously been problematical