Inhibition of interleukin-1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

OBJECTIVE: To assess the capacities of the cytokine inhibitors interleukin-1 receptor antagonist (IL-1Ra; anakinra) and PEGylated soluble tumor necrosis factor receptor I (PEG sTNFRI; pegsunercept) to suppress neovascularization. METHODS: A corneal angiogenesis assay was performed by implanting nylon discs impregnated with an angiogenic stimulator (basic fibroblast growth factor or vascular endothelial growth factor) into one cornea of female Sprague-Dawley rats. Animals were treated with IL-1Ra or PEG sTNFRI for 7 days, after which new vessels were quantified. In a parallel study, male Lewis rats with mycobacteria-induced adjuvant-induced arthritis were treated with IL-1Ra or PEG sTNFRI for 7 days beginning at disease onset, after which scores for inflammation and bone erosion as well as capillary counts were acquired from sections of arthritic hind paws. RESULTS: Treatment with IL-1Ra yielded a dose-dependent reduction in growth factor-induced corneal angiogenesis, while PEG sTNFRI did not. IL-1Ra, but not PEG sTNFRI, significantly reduced the number of capillaries in arthritic paws, even though both anticytokines reduced inflammation and bone erosion to a similar degree. CONCLUSION: These data support a major role for IL-1, but not TNFalpha, in angiogenesis and suggest that an additional antiarthritic mechanism afforded by IL-1 inhibitors, but not anti-TNF agents, is the suppression of the angiogenic component of pannus.     

Nigrostriatal lesion and dopamine agonists affect firing patterns of rodent entopeduncular nucleus neurons

Altered activity of the entopeduncular nucleus, the rodent homologue of the globus pallidus internal segment in primates, is thought to mediate behavioral consequences of midbrain dopamine depletion in rodents. Few studies, however, have examined dopaminergic modulation of spiking activity in this nucleus. This study characterizes changes in entopeduncular neuronal activity after nigrostriatal dopaminergic lesion and the effects of systemic treatment with selective D(1) (SKF 38393) and D(2) (quinpirole) agonists in lesioned rats. Extracellular single-unit recordings were performed in awake immobilized rats, either in neurologically intact animals (n = 42) or in animals that had received unilateral 6-hydroxydopamine infusion into the medial forebrain bundle several weeks previously (n = 35). Nigrostriatal lesion altered baseline activity of entopeduncular neurons in several ways. Interspike interval distributions had significantly decreased modes and significantly increased coefficient of variation, skewness and kurtosis; yet interspike interval mean (the inverse of firing rate) was not affected. Also, spectral analysis of autocorrelograms indicated that lesion significantly reduced the incidence of regular-spiking neurons and increased the incidence of neurons with 4-18 Hz oscillations. Dopamine agonist treatment reversed some lesion-induced effects: quinpirole reversed changes in interspike interval distribution mode and coefficient of variation, while combined quinpirole and SKF 38393 blocked the appearance of 4-18 Hz oscillations. However, no agonist treatment normalized all aspects of entopeduncular activity. Additionally, inhibition of firing rates by D(1) or combined D(1)/D(2) receptor activation indicated that dopamine agonists affected the overall level of entopeduncular activity in a manner similar to that found in the substantia nigra pars reticulata and globus pallidus internal segment after dopamine neuron lesion. These data demonstrate that lesion of the nigrostriatal tract leads to modifications of several aspects of firing pattern in the rodent entopeduncular nucleus and so expand on similar findings in the rodent substantia nigra pars reticulata and in the globus pallidus internal segment in humans and nonhuman primates. The results support the view that dysfunction in the basal ganglia after midbrain dopamine neuron loss relates more consistently to abnormal activity patterns than to net changes in firing rate in the basal ganglia output nuclei, while overall decreases in firing rate in these structures may play a more important role in adverse motor reactions to dopamine agonist treatments.     

Genomic localization of a T serotype locus to a recombinatorial zone encoding extracellular matrix-binding proteins in Streptococcus pyogenes

Streptococcus pyogenes is an important bacterial pathogen afflicting humans. A striking feature is its extraordinary biological diversity, evident in the wide range of diseases it can cause and the antigenic heterogeneity present on its surface. The T antigens form the basis of a major serological typing scheme that is often used as an alternative or supplement to M typing. Unlike M typing, the genetic basis for T typing is poorly understood. In this report, the tee6 gene is localized to a position approximately equal to 3.3 kb downstream from prtF1 (or sfbI), which encodes the Fn-binding protein, protein F, a key virulence factor. Comparison of this portion of the genome with those of four additional strains reveals the presence of genes encoding a collagen-binding protein (Cpa) and a second Fn-binding protein (PrtF2 or PfbpI). This chromosomal region--here designated the FCT region--is approximately 11 to 16 kb in length and is flanked at both ends by long stretches of highly conserved sequence. For each of the five strains, the FCT region contains a unique combination of semiconserved loci, indicative of extensive intergenomic recombination. The data provide evidence that the highly recombinatorial FCT region of the S. pyogenes genome is under strong selection for change in response to the host environment.     

Professional responsibility in relation to cervical spine manipulation

Manipulation of the cervical spine is one of the few potentially life-threatening procedures performed by physiotherapists. Is it worth the risk? A comparison of risks versus benefits indicates that at present, the risks of cervical manipulation outweigh the benefits: manipulation has yet to be shown to be more effective for neck pain and headache than other interventions such as mobilisation, whereas the risks, although infrequent, are serious. This analysis is of particular concern because the conditions for which manipulation is indicated are benign and usually self-limiting. Because physiotherapists have legal and ethical obligations to the community to avoid foreseeable harm and provide optimum care, it may be prudent to determine who in our profession should perform cervical manipulation. That is, the profession could restrict the practice of cervical spine manipulation. Although all registered physiotherapists in Australia are entitled to perform cervical manipulation, few choose to use this intervention. Therefore, it might be feasible to encourage those practitioners who wish to use cervical manipulation to undertake formal education programs. Such a requirement could be embodied in a code of practice that discourages those without formal training from performing cervical manipulation. By taking such measures, we could ensure that our profession exercises wisdom in its monitoring and use of cervical manipulation.