IL-12 and IL-23: master regulators of innate and adaptive immunity

Summary: Initiation of an effective immune response requires close interactions between innate and adaptive immunity. Recent advances in the field of cytokine biology have led to an increased understanding of how myeloid cell‐derived factors regulate the immune system to protect the host from infections and prevent tumor development. In this review, we focus on the function of interleukin (IL)‐23, a new member of the IL‐12 family of regulatory cytokines produced by activated macrophages and dendritic cells. We propose that IL‐12 and IL‐23 promote two distinct immunological pathways that have separate but complementary functions. IL‐12 is required for antimicrobial responses to intracellular pathogens, whereas IL‐23 is likely to be important for the recruitment and activation of a range of inflammatory cells that is required for the induction of chronic inflammation and granuloma formation. These two cytokines work in concert to regulate cellular immune responses critical for host defense and tumor suppression.     

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.     

The effect of central corneal thickness on estimates of the anterior chamber depth

Background: The slitlamp can be used to estimate the anterior chamber depth (ACD). The length of a slit object is increased until the corneal and iris/lens images appear to just touch. Multiplying the just‐touching‐slit‐length (JTSL) by a conversion factor gives an estimate of the ACD as measured by ultrasonography. The purpose of this study was to determine if central corneal thickness (CCT) affects the accuracy of this technique. Methods: The ACD of 50 subjects was measured by A‐scan ultrasonography and estimated by the slitlamp technique. CCT was measured by ultrasonic pachometry. The refractive error was determined subjectively. Results: The average ultrasonographic ACD for all subjects was 3.32 ± 0.65 mm. The average JTSL was 2.46 ± 0.38 mm. The conversion ratio between the ultrasonographic ACD and the average JTSL was 1.35. The predicted ACD using the regression equation of JTSL on the ultrasound anterior chamber depth (USACD) was 3.32 ± 0.54 mm. The corresponding value using the regression equation of JTSL and CCT on USACD was exactly the same, that is, 3.32 ± 0.54 mm. Conclusion: Incorporation of CCT into a regression equation does not improve the accuracy of the Smith technique.     

The effect of ward design on the well-being of post-operative patients

Changes in the design of hospital wards have usually been determined by architects and members of the nursing and medical professions, the views and preferences of patients have seldom been sought directly The Hospital Anxiety and Depression scale and the Disturbance Due to Hospital Noise questionnaire were administered to 64 female patients on bay and Nightingale wards together with a questionnaire designed for this study Perceptions of social and physical factors of ward design were examined, and their relationship to psychological well-being and sleep patterns The results show that the bay ward seemed to offer a more favourable environment for patients but some of the disadvantages of bay wards are balanced by better staffing levels and better and more modern facilities Visibility to nurses was lower on the bay ward The Nightingale ward was perceived as significantly noisier than the bay ward and noise levels were significantly correlated to anxiety scores Paradoxically the increase in noise levels appeared to improve the perceived level of privacy on the Nightingale ward Seventy-five per cent of patients were found to prefer the bay ward design, and since neither design appears to have major disadvantages their continued introduction should be encouraged However, recommendations are made concerning the optimizing of patients' well-being within the bay ward setting     

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Balance and recovery from a perturbation are impaired in people with functional ankle instability.

OBJECTIVE: To determine if differences in balance and recovery would be found between controls and participants with unilateral or bilateral functional ankle instability (FAI). DESIGN: Cross-Sectional Study. SETTING: University laboratory and Community premises. PARTICIPANTS: Twenty healthy participants(C), 19 participants with unilateral FAI [both the uninjured (UC) and unstable ankle (UI) were included] and 22 participants with bilateral FAI (BI). MAIN OUTCOME MEASURES: Balance was measured in single leg stance as: number of part foot lifts in 30 s; magnitude of medio-lateral ankle movement in two foot positions; and ability to balance on the ball of the foot. Recovery was determined by time to return to baseline medio-lateral ankle movement after a 15 degree inversion perturbation. RESULTS: The controls lifted the foot fewer times than the other three groups [C = 12.7 +/- 1.8 (mean +/- SE) foot lifts, UC = 22.9 +/- 2.5, UI = 25.1 +/- 2.3, and BI = 21.1 +/- 2.2, t-test, P = 0.006] and recovered significantly faster than the unstable ankles [C = 1.53 +/- 0.42 sec (median +/- SE), UI = 2.34 +/- 0.30 sec, BI = 2.15 +/- 0.70 sec, P < 0.02]. With FAI measured by the Cumberland Ankle Instability Tool, the external control group balanced on demi-pointe better than both instability groups (P < 0.05), and recovered quicker than all groups. CONCLUSION: There are differences in balance and recovery between external controls and participants with both unilateral and bilateral FAI but not between the legs of participants with unilateral FAI.     

A Review of Staffing in Childcare Centres in Six Countries

A review of the international literature on staffing in childcare centres in five English language countries and Denmark reveals both remarkable similarities and interesting differences in the childcare workforce. The paper compares characteristics of the workforce; their training and professional membership. It also compares conditions of work in each country, including salaries, staff benefits, and features of the working environment such as job satisfaction and staff turnover. Findings indicate that childcare workers tend to be young and female; that a relatively high proportion of untrained staff work in childcare centres; that, except in Denmark, the level of extrinsic benefits is startlingly low. Workers are paid relatively little compared to the average pay for women in their countries but the workforce does not benefit from enhanced conditions of work to compensate for low pay. However, the level of intrinsic satisfaction with the work is high. Caring for children is a satisfying form of employment, even if it offers a limited career structure.     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.