An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models.

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.     

Rotigotine transdermal patch in early Parkinson's disease: a randomized, double-blind, controlled study versus placebo and ropinirole.

Rotigotine is a new, non-ergot dopamine agonist formulated in a transdermal delivery system. The present study was to investigate the efficacy and safety of the rotigotine transdermal patch in the treatment of early Parkinson's disease. Patients (n = 561) were randomized to rotigotine, ropinirole, or placebo. The titration period was up to 13 weeks, and there was a minimum dose-maintenance period of 24 weeks for ropinirole and 33 weeks for rotigotine. The primary endpoint was the proportion of patients with a minimum of 20% decrease in the combined Unified Parkinson's Disease Rating Scale Part II and Part III scores. The responder rate in the rotigotine group was significantly higher than in the placebo group (52% vs. 30%, P < 0.0001). Transdermal rotigotine at doses < or =8 mg/24 h did not show noninferiority to ropinirole at doses < or =24 mg/day. In a post-hoc subgroup analysis, rotigotine < or =8 mg/24 hours had a similar efficacy to ropinirole at doses < or =12 mg/day. The rotigotine transdermal patch was well tolerated. The most common adverse events were application-site reactions, nausea, and somnolence. Application-site reactions were predominantly mild or moderate in intensity. In conclusion, the rotigotine transdermal patch represents an effective and safe option for the treatment of patients with early Parkinson's disease.     

Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity.

The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It has been suggested that this system of thermogenesis can provide a defense against obesity. To test this idea, we created a transgenic mouse in which the fat-specific aP2 gene promoter directed Ucp expression in white fat and provided for the constitutive expression of Ucp in brown fat. Transgenic mice showed both Ucp mRNA and immunoreactive UCP in white fat at 2-10% the level normally measured in brown fat. A reduction in subcutaneous fat of aP2-Ucp C57BL/6J mice was observed at 3 mo of age. When the transgene was expressed in Avy genetically obese mice reductions in total body weight and subcutaneous fat stores were observed. Female transgenic Avy mice at 13 mo of age weighed 35 grams, a weight indistinguishable from nontransgenic C57BL/6J mice. Gonadal fat showed an increase in a novel adipocyte derivative that did not accumulate lipids and that constituted approximately 80% of the mass of the tissue in Avy transgenic. A major effect of aP2-Ucp in brown fat was to reduce endogenous gene expression by as much as 95%. The results suggest that UCP synthesized from the aP2 gene promoter is thermogenically active and capable of reducing fat stores.     

Acute effects of ultraviolet-B irradiation on the corneal surface of the pigmented rabbit studied by quantitative scanning electron microscopy

The eyes of female pigmented rabbits were exposed to a single dose of UV-B (300 +/- 9 nm, 0.05 J/cm2 total dose) between 13.30 and 15.00 h. The average irradiance was 225 +/- 36 microW/cm2 delivered over 191 to 264 s. At various time periods thereafter (24, 48, 72 and 96 h post-irradiation), the animals were euthanized by pentobarbital overdose and the eyes fixed with 2% glutaraldehyde in 80 mM cacodylate buffer (pH 7.4, total osmolarity of 330-340 mOsm/L). Corneal quadrants were examined by high resolution scanning electron microscopy at 100 X and 500 X at-stage magnification at central, mid-peripheral and peripheral sites. The micrographs from the central cornea were subjected to a quantitative analysis using a computer based digitization system. A peak effect was observed at 48 h at which cellular exfoliation was noted at the corneal apex. In the region immediately adjacent to the exfoliating cells, the number of light and dark electron reflex cells decreased to 48 h while the numbers of medium-reflex cells decreased after 48 h. The relative surface area of all cells was also decreased at 48 h compared to unirradiated controls. Significant recovery was observed by 96 h. Mid-peripheral and peripheral sites were largely unaffected by this just supra-threshold irradiation.     

Cloning and characterisation of the adenosyl phosphosulphate kinase gene from Aspergillus nidulans

The sD gene of Aspergillus nidulans has been cloned by heterologous screening of rationally selected cosmids. Co-transformation of the sD50 mutant JMP1 confirmed the presence of a functional gene. Sequence analysis determined this gene to be 680 bp in length, containing a 59-bp intron and encoding a protein of 206 amino acids. A protein-sequence comparison revealed a similarity to the C-terminal region of ATP sulphurylase, the sC gene product. Further sequence comparison revealed differences in a consensus sequence ATP-binding motif, indicating non-functionality of the APS kinase-like domain of ATP sulphurylase, and confirms sD as the gene encoding APS kinase in A. nidulans. Received: 17 April / 29 August 1997     

A nocturnal nasogastric feeding programme in cystic fibrosis adults

Fourteen adult patients (mean age 22.5 years, range 18–35) with cystic fibrosis undertook nocturnal nasogastric feeding for a mean period of 14.7 (range 6–18) months consuming an average of 1042 ml of a high energy feed on five nights of each week. Following this protocol all patients gained weight (mean weight gain 5.4 kg, range 2–17). For the group as a whole, lung function remained stable during the period of feeding; however a significant correlation between improvement in lung function and weight gain was demonstrated. Hyperglycaemia during feeding in this adult population was common (9/14, 64%) but was easily controlled with insulin therapy.     

Osteointegration of bone graft in porous-coated total hip arthroplasty

Since 1983, 19 patients have had bone grafting of acetabular defects in association with a porous-coated acetabular prosthesis. The defects were defined by anatomic location to assess the rates of incorporation at different sites. The average time to incorporation was 12 months, judged by trabecular continuity. Superolateral grafts showed a greater degree of rarefaction than medial grafts. Nonprogressive migration of the graft was seen in only two cases before full incorporation of the graft. Developing lucency was seen up to 2 mm at the prosthesis-graft interface but not at the graft-ilium level. Roentgenograms suggested that integration of porous acetabular prostheses into bone may improve results of reconstructive surgery of the acetabulum.     

An application of capture-recapture methods to the estimation of completeness of cancer registration

Completeness of cancer registration has not been consistently ascertained across different registries. This report describes how capture-recapture methods have been used to estimate completeness at the Ontario Cancer Registry. The method was applied in two fashions; first, using three data sources in a modeling approach: and second, using two data sources and standard, simple capture-recapture methods. The modeling approach is more flexible, since several variables that influence cancer registration can be considered and can be used to identify reporting patterns of different data sources. In the present analysis, estimates of completeness of the registry as a whole were remarkably similar using either two or three data sources, and site-specific comparisons differed by at most 7%. Because of the advantages of capture-recapture methods-estimation of level of completeness, possible comparability of estimates across different registries, and versatility to consider other determinants of cancer registration-a plea for greater use of these methods in cancer registration is made.