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.     

Skin cancers and precancerous lesions in Parkinson's disease patients.

Our objective was to evaluate the frequency of neoplastic and preneoplastic skin lesions in Parkinson's disease (PD) patients when compared with an aged-matched population. We performed a cross-sectional survey in PD patients and in an age-matched control group. Patients and controls were examined by a movement disorder specialist and a dermatologist. 150 PD patients and 146 controls were included. Thirty-five PD patients (23.3%) presented skin lesions that could be classified as neoplastic or preneoplastic vs. 20 subjects in the control group (13.7%) (OR 95%, CI 1.92 [1.05, 3.51]). However, this difference lost statistical significance when adjusted for gender (recruitment of controls was matched just for age with an over representation of males in the PD group). Twenty-nine PD patients (19%) presented actinic keratosis and basal cell carcinoma was diagnosed in 4 patients (3%). Although nonconclusive, our results are in agreement with previous studies suggesting an increased risk of skin cancer in PD patients. The frequency of actinic keratosis in PD patients and the associated risk to develop melanoma recommends its screening in future epidemiological studies.     

Fructose metabolism in the adult mouse optic nerve, a central white matter tract.

Our recent report that fructose supported the metabolism of some, but not all axons, in the adult mouse optic nerve prompted us to investigate in detail fructose metabolism in this tissue, a typical central white matter tract, as these data imply efficient fructose metabolism in the central nervous system (CNS). In artificial cerebrospinal fluid containing 10 mmol/L glucose or 20 mmol/L fructose, the stimulus-evoked compound action potential (CAP) recorded from the optic nerve consisted of three stable peaks. Replacing 10 mmol/L glucose with 10 mmol/L fructose, however, caused delayed loss of the 1st CAP peak (the 2nd and 3rd CAP peaks were unaffected). Glycogen-derived metabolic substrate(s) temporarily sustained the 1st CAP peak in 10 mmol/L fructose, as depletion of tissue glycogen by a prior period of aglycaemia or high-frequency CAP discharge rendered fructose incapable of supporting the 1st CAP peak. Enzyme assays showed the presence of both hexokinase and fructokinase (both of which can phosphorylate fructose) in the optic nerve. In contrast, only hexokinase was expressed in cerebral cortex. Hexokinase in optic nerve had low affinity and low capacity with fructose as substrate, whereas fructokinase displayed high affinity and high capacity for fructose. These findings suggest an explanation for the curious fact that the fast conducting axons comprising the 1st peak of the CAP are not supported in 10 mmol/L fructose medium; these axons probably do not express fructokinase, a requirement for efficient fructose metabolism.     

Glatiramer acetate in the treatment of multiple sclerosis

Glatiramer acetate is an immunomodulating drug used in the treatment of multiple sclerosis. It consists of a copolymer of amino acid residues in the same stoichiometric proportions as in myelin basic protein. Its mechanism of action is not entirely known and is probably multifaceted, with deletion of some immune cell populations and stimulation of others in these patients. Some mechanisms involve neuroprotectant effects. There is ample evidence of its efficacy in relapsing-remitting disease, using both clinical and imaging measures of disease activity, and in this paper we review the clinical and basic studies of this drug. Finally we discuss how some of its neuroprotectant effects may be useful in neurodegeneration such as is seen in more advanced cases of multiple sclerosis and other diseases such as amyotrophic lateral sclerosis and Parkinson’s disease.     

Is chronic nitrate therapy associated with a different clinical presentation of acute coronary syndrome?

BACKGROUND: Nitrate therapy can induce ischemic preconditioning with a consequent increase in tolerance to ischemia. In the context of acute coronary syndromes (ACS), nitrates may result in a different presentation. with greater protection. OBJECTIVES: To investigate in a population of patients with ACS whether previous chronic use of nitrates results in a different presentation of ACS. METHODS: We studied 287 patients (65 +/- 13 years, 66% male) admitted to our department in the first six months of 2005 with ACS (with and without ST-segment elevation). Of these, 8% were under nitrate therapy at the time of admission. In this group, 27% presented ACS without ST-segment elevation, while in the group without nitrates this value was 58% (p = 0.005). By univariate analysis, the use of nitrates was a predictor of the preferential occurrence of non-ST-segment elevation ACS (OR 0.27, 95% CI 0.10-0.71). After correction for the potential influence of variables (age, gender, previous revascularization and smoking) by multivariate logistic regression, nitrate therapy remained a borderline predictor of clinical presentation as non-ST-segment elevation ACS (OR 0.37, 95% CI 0.13-1.04, p = 0.059). CONCLUSIONS: Previous use of nitrates was associated with a tendency to present as non-ST-segment elevation ACS. This finding may be explained by the hypothesis that nitrates induce pharmacological preconditioning, reducing the transmural extent of myocardial infarction.     

Thyroid disease and pregnancy: degrees of knowledge.

OBJECTIVE: The literature on the impact of thyroid abnormalities on pregnancy and the postpartum has expanded rapidly over the last two decades. The objective of the present study was to determine the level of knowledge of endocrinologists, obstetrician/gynecologists, internists, and family physicians in regard to thyroid disease and pregnancy. DESIGN: A 16-item questionnaire on issues related to thyroid disease and pregnancy was developed. Endocrinologists (n = 116), obstetrician/gynecologists (n = 81), internists (n = 109), and family physicians (n = 99) were asked to complete the questionnaire. Physician self-report of confidence regarding degree of knowledge was obtained through completion of a seven-point Likert scale. MAIN OUTCOME: The percentage of questions answered correctly by all physicians was 63%. Endocrinologists had the highest correct response rate (77%), followed by obstetrician/gynecologists. Hierarchical regression analysis revealed that medical specialty, years of training, confidence level, and whether or not the physician treated pregnant women were significantly related to the overall score. CONCLUSIONS: The present study demonstrates a suboptimal level of knowledge regarding thyroid disease and pregnancy among physicians in four specialties. A comprehensive physician education program is needed.     

Incorporation of protein-eluting microspheres into biodegradable nerve guidance channels for controlled release.

Nerve guidance channels (NGCs) promote axonal regeneration after transection injury of the peripheral nerve or spinal cord, yet this regeneration is limited. To enhance regeneration further, we hypothesize that localized delivery of therapeutic molecules combined with the NGC is required. In an attempt to achieve such an NGC, we designed and synthesized a novel NGC in which protein-encapsulated microspheres were stably incorporated into the tube wall. Specifically, poly(lactide-co-glycolide) (PLGA 50/50) microspheres were physically entrapped in the annulus between two concentric tubes, consisting of a chitosan inner tube and a chitin outer tube. Taking advantage of the extensive shrinking that the outer chitin tube undergoes with drying, >15 mg of microspheres were loaded within the tube walls. Using BSA-encapsulated microspheres as the model drug delivery system, BSA was released from microsphere loaded tubes (MLTs) for 84 days, and from freely suspended PLGA microspheres for 70 days. An initial burst release was observed for both MLTs and free microspheres, followed by a degradation-controlled release profile that resulted in a higher release rate from MLTs initially, which was then attenuated likely due to the buffering effect of chitin and chitosan tubes. Epidermal growth factor (EGF), co-encapsulated with BSA in PLGA 50/50 microspheres in MLTs, was released for 56 days with a similar profile to that of BSA. Released EGF was found to be bioactive for at least 14 days as assessed by a neurosphere forming bioassay.     

Human papillomavirus and HIV coinfection and the risk of neoplasias of the lower genital tract: a review of recent developments

ONE OF THE RISK FACTORS FOR HUMAN PAPILLOMAVIRUS (HPV) INFECTION and subsequent lower genital tract neoplasias and cancers is impaired cell-mediated immunity. HIV-positive women with severe immunosuppression are 5 times more likely than HIV-negative women to have lower genital tract neoplasias. A corresponding increase in the risk of invasive vulvar and anal cancers, but not of cervical cancer, has also been observed among HIV-positive women. Treatment failure and recurrence of neoplasia occur much more frequently among HIV-positive than among HIV-negative women. In this review, we discuss recent advances in the understanding of the relation between HIV and HPV coinfection and the development of lower genital tract neoplasias and cancers in women. In addition, we present strategies for monitoring and treating noninvasive and invasive neoplasias of the lower genital tract in HIV-positive women.     

Genomic ancestry of a sample population from the state of São Paulo,Brazil

Allelic frequencies of eight autosomal short‐tandem repeat (STR) loci (TH01, TPOx, CSF1PO, vWA, FES/FPS, F13A1, F13B, and CD4) were determined in 400 individuals born in the State of São Paulo. No significant deviations from Hardy‐Weinberg equilibrium were found in any loci analyzed. The Unweighted Pair‐Group Method with Arithmetic Mean (UPGMA) tree constructed based on genetic distances revealed that the present population was grouped with Europeans, and separated from African and Amerindian populations. Estimates of admixture components based on the gene identity method revealed 79% European, 14% African, and 7% Amerindian contributions to this Brazilian population sample. Am. J. Hum. Biol. 18:702–705, 2006. © 2006 Wiley‐Liss, Inc.