Deactivation of endothelium and reduction in angiogenesis in psoriatic skin and synovium by low dose infliximab therapy in combination with stable methotrexate therapy: a prospective single-centre study

Psoriasis and psoriatic arthritis are inflammatory diseases that respond well to anti-tumour necrosis factor-α therapy. To evaluate the effects of anti-tumour necrosis factor-α treatment on expression of adhesion molecules and angiogenesis in psoriatic lesional skin and synovial tissue, we performed a prospective single-centre study with infliximab therapy combined with stable methotrexate therapy. Eleven patients with both active psoriasis and psoriatic arthritis received infusions of infliximab (3 mg/kg) at baseline, and at weeks 2, 6, 14 and 22 in an open-label study. In addition, patients continued to receive stable methotrexate therapy in dosages ranging from 5 to 20 mg/week. Clinical assessments, including Psoriasis Area and Severity Index (PASI) and Disease Activity Score (DAS), were performed at baseline and every 2 weeks afterward. In addition, skin biopsies from a target psoriatic plaque and synovial tissue biopsies from a target joint were taken before treatment and at week 4. Immunohistochemical analysis was performed to detect the number of blood vessels, the expression of adhesion molecules and the presence of vascular growth factors. Stained sections were evaluated by digital image analysis. At week 16, the mean PASI was reduced from 12.3 ± 2.4 at baseline to 1.8 ± 0.4 (P ≤ 0.02). The mean DAS was reduced from 6.0 ± 0.5 to 3.6 ± 0.6 (P ≤ 0.02). We found some fluctuations in DAS response as compared with the change in PASI, with the latter exhibiting a steady decrease over time. After 4 weeks the cell infiltrate was reduced in both skin and synovium. There was a significant reduction in the number of blood vessels in dermis and synovium at week 4. A significant reduction in the expression of α_vβ₃ integrin, a marker of neovascularization, was also found in both skin and synovium at week 4. In addition, a significant reduction in the expression of adhesion molecules was observed in both skin and synovium at week 4. We also observed a trend toward reduced expression of vascular endothelial growth factor in both skin and synovium. In conclusion, low-dose infliximab treatment leads to decreased neoangiogenesis and deactivation of the endothelium, resulting in decreased cell infiltration and clinical improvement in psoriasis and psoriatic arthritis.     

Sevoflurane suppresses noxious stimulus-evoked expression of Fos-like immunoreactivity in the rat spinal cord via activation of endogenous opioid systems

We investigated the antagonism of sevoflurane antinociception by opioid antagonists in the rat formalin test. Formalin injection into the hindpaw of the rat induces the nocifensive flinching behavior and the expression of Fos-like immunoreactivity (Fos-LI) in the spinal cord. Sevoflurane significantly suppressed the flinching behavior and decreased the number of Fos-LI neurons in the dorsal horn of spinal cord compared with the control group. Moreover, pretreatment with intraperitoneal naloxone plus naltrexone antagonized the suppression of flinching behavior and the decrease of the number of Fos-LI neurons produced by 3% sevoflurane. Intraperitoneal opioid antagonists themselves had no effects on both the behavior response and the expression of Fos-LI induced by formalin injection. This study supports the hypothesis that sevoflurane suppresses the nociceptive response, at least in part, by activating endogenous opioid systems.     

N and P colimitation of N2-fixing and N-supplied fynbos legumes from the Cape Floristic Region

Background and aims

Legume species in the fynbos vegetation of the Cape Floristic Region, that fix N₂ in soils with low P, may have evolved for enhanced acquisition and efficient use of P. It was hypothesized that N₂-fixing and combined-N supplied (N-supplied) A. linearis, P. calyptrata and C. genistoides are adapted to low P and would be relatively unresponsive to increased P of 100 μM.

Methods

18 legume species were evaluated for their nodulation response to low P availability. The N X P interaction was then examined in A. linearis, P. calyptrata and C. genistoides reliant on either N₂-fixation or 300 μM N (NH₄NO₃), and receiving 0.1, 1.0, 10 and 100 μM P (NaH₂PO₄).

Results

In the species selection experiment, A. linearis, P. calyptrata and C. genistoides, with the greatest nodule fresh weight (FW) and nodule FW to root FW ratio, were the most prolific nodulating species. In the N X P experiment, with low P supply, the biomass of N₂-fixing P. calyptrata and C. genistoides was consistently greater than that of N-supplied plants. In contrast, with high P supply of 100 μM P, all N-supplied plants accumulated more biomass than the corresponding N₂-fixing plants. High P-use efficiency, poor down-regulation of P uptake and P storage was evident in A. linearis and P. calyptrata.

Conclusion

The growth response to P and the significant N X P interactions indicate that N₂-fixing and N-supplied plants were not adapted to low P, but rather colimited by both N and P.     

A PATO-compliant zebrafish screening database (MODB): management of morpholino knockdown screen information

Background  

The zebrafish is a powerful model vertebrate amenable to high throughput in vivo genetic analyses. Examples include reverse genetic screens using morpholino knockdown, expression-based screening using enhancer trapping and forward genetic screening using transposon insertional mutagenesis. We have created a database to facilitate web-based distribution of data from such genetic studies.     

Loss of phylogenetic information in chorion gene families of Bombyx mori gene conversion

The silkmoth chorion has provided a stimulating model for the study of evolution and developmental regulation of gene families. Previous attempts at inferring relationships among chorion sequences have been based on pairwise comparisons of overall similarity, a potentially problematic approach. To remedy this, we identified the alignable regions of low sequence variability and then analyzed this restricted database by parsimony and neighbor-joining methods. At the deepest level, the chorion sequence tree is split into two branches, called "alpha" and "beta." Within each branch, early- and late-expressing genes each constitute monophyletic groups, while the situation with middle-expressing genes remains uncertain. The HcB gene family appears to be the most basal beta-branch group, but this conclusion is qualified because the effect of gene conversion on branching order is unknown. Previous studies by Eickbush and colleagues have strongly suggested that ErA, HcA, and HcB families undergo gene conversion within a gene family, whereas the ErB family does not. The occurrence of conversion correlates with a particular tree structure; namely, branch lengths are much greater at the base of the family than at higher internodes and terminal branches. These observations raise the possibility that chorion gene families are defined by gene conversion events (reticulate evolution) rather than by descent with modification (synapomorphy).      

History of Pine Wilt Disease in Japan

Pine wilt disease induced by the pinewood nematode, Bursaphelenchus xylophilus, is a great threat to pine forests in Japan. The first occurrence of the disease was reported in Nagasaki, Kyushu. During the 1930s the disease occurrence was extended in 12 prefectures, and in the 1940s the disease was found in 34 prefectures. The annual loss of pine trees increased from 30,000 m³ to 1.2 million m³ during these two decades. The enormous increase in timber loss in the 1970s resulted in 2.4 million m³ of annual loss in 1979. The affected area expanded into 45 prefectures of 47 prefectures in Japan. In cool areas the disease differs in epidemiology from that in heavily infested areas in the warm regions. A national project for controlling pine wilt disease lays special emphasis on the healthy pine forests predominating throughout cool areas in northern Japan.     

Unravelling developmental disregard in children with unilateral cerebral palsy by measuring event-related potentials during a simple and complex task

Background

In a subset of children with unilateral Cerebral Palsy (CP) a discrepancy between capacity and performance of the affected upper limb can be observed. This discrepancy is known as Developmental Disregard (DD). Though the phenomenon of DD has been well documented, its underlying cause is still under debate. DD has originally been explained based on principles of operant conditioning. Alternatively, it has been proposed that DD results from a diminished automaticity of movements, resulting in an increased cognitive load when using the affected hand. To investigate the amount of involved cognitive load we studied Event-Related Potentials (ERPs) preceding task-related motor responses during a single-hand capacity and a dual-hand performance task. It was hypothesised that children with DD show alterations related to long-latency ERP components when selecting a response with the affected upper limb, reflecting increased cognitive load in order to generate an adequate response and especially so within the dual-hand task.

Methods

Fifteen children with unilateral CP participated in the study. One of the participants was excluded due to major visual impairments. Seven of the remaining participants displayed DD. The other seven children served as a control group. All participants performed two versions of a cue-target paradigm, a single-hand capacity and a dual-hand performance task. The ERP components linked to target presentation were inspected: the mid-latency P2 component and the consecutive long-latency N2b component.

Results

In the dual-hand performance task children with DD showed an enhancement in mean amplitude of the long-latency N2b component when selecting a response with their affected hand. No differences were found regarding the amplitude of the mid-latency P2 component. No differences were observed regarding the single-hand capacity task. The control group did not display any differences in ERPs linked to target evaluation processes between both hands.

Conclusion

These electrophysiological findings show that DD is associated with increased cognitive load when movements are prepared with the affected hand during a dual-hand performance task. These findings confirm behavioural observations, advance our insights on the neural substrate of DD and have implications for therapy.     

Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial

Background

In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain. The primary aim of the FACTS-2-FSHD (acronym for Fitness And Cognitive behavioural TherapieS/for Fatigue and ACTivitieS in FSHD) trial is to study the effect of AET and CBT on the reduction of chronic fatigue as assessed with the Checklist Individual Strength subscale fatigue (CIS-fatigue) in patients with FSHD. Additionally, possible working mechanisms and the effects on various secondary outcome measures at all levels of the International Classification of Functioning, Disability and Health (ICF) are evaluated.

Methods/Design

A multi-centre, assessor-blinded, randomized controlled trial is conducted. A sample of 75 FSHD patients with severe chronic fatigue (CIS-fatigue ≥ 35) will be recruited and randomized to one of three groups: (1) AET + usual care, (2) CBT + usual care or (3) usual care alone, which consists of no therapy at all or occasional (conventional) physical therapy. After an intervention period of 16 weeks and a follow-up of 3 months, the third (control) group will as yet be randomized to either AET or CBT (approximately 7 months after inclusion). Outcomes will be assessed at baseline, immediately post intervention and at 3 and 6 months follow up.

Discussion

The FACTS-2-FSHD study is the first theory-based randomized clinical trial which evaluates the effect and the maintenance of effects of AET and CBT on the reduction of chronic fatigue in patients with FSHD. The interventions are based on a theoretical model of chronic fatigue in patients with FSHD. The study will provide a unique set of data with which the relationships between outcome measures at all levels of the ICF could be assessed.

Trial registration

Dutch Trial Register, NTR1447.