Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata

L-DOPA is the most effective pharmacological agent used for the symptomatic treatment of Parkinson's disease but long-term L-DOPA treatment induces involuntary abnormal movements such as dyskinesias. The present study, using in vivo microdialysis, investigated the effects of a single or subchronic administration of L-DOPA to adult rats with a unilateral 6-OHDA lesion of dopamine neurons on GABA release in the substantia nigra, pars reticulata (SNr). The results indicate that a challenge injection of L-DOPA (50 mg/kg, i.p.) significantly increases GABA levels in the SNr of rats treated with a daily repeated administration of L-DOPA (50 mg/kg, i.p.). Further statistical analysis between groups also showed that extracellular GABA levels were significantly higher in the subchronic L-DOPA group than in the group receiving only one injection of L-DOPA. These results show that the subchronic administration of L-DOPA results in a sensitization of enhanced extracellular GABA levels in the SNr.     

Interleukin 23 is critical in the pathogenesis of spondyloarthropathy and acts on a novel population of interleukin 23R+ entheseal resident cells

Spondyloarthropathy is characterised by inflammation, bone erosion, and new bone formation at the entheseal insertions of tendons and ligaments to bone. Lack of understanding of the underlying mechanisms that drive entheseal disease has seriously inhibited design of therapeutics. Although anti-tumour necrosis factor (TNF) therapy reduces signs and symptoms of inflammation, residual inflammation continues and bone growth is not inhibited. This suggests that TNF is not the optimum target to modify entheseal disease.We previously demonstrated that interleukin (IL) 23 is pivotal in autoimmune inflammation. Recently, genetic variants in the IL-23 receptor (IL23R) have been associated with development of spondyloarthropathy. Moreover, HLA-B27 (present in 90% of patients with ankylosing spondylitis) as well as associated bowel inflammation have been shown to induce IL-23 expression. However, the site and mechanism of action of IL23 are unknown and the reason why such dysregulation of IL23 is associated with inflammation specifically at the enthesis has been inexplicable. We now demonstrate that the entheses and aortic root contain a novel population of resident IL23R+ T cells, which allow the tissue to rapidly respond to IL23. Intravital microscopy reveals that these cells display an extremely restricted entheseal localisation and are absent from synovium and tendon proper. The cells express the molecule PLZF, which allows them to respond to cytokines extremely rapidly, and indeed entheses respond within hours to IL23 in vitro. Moreover, IL-23 expression in vivo in mice is sufficient by itself to rapidly induce the hallmark features of spondyloarthropathy with development of exceedingly specific enthesitis, aortitis, and typical bone erosion and new bone formation.The highly restricted distribution of IL23R+ cells provides the fundamental basis for the anatomical localisation of inflammation observed in spondyloarthropathy, as well as allowing a unified understanding of the genetic associations. These findings suggest that neutralisation of IL23 may be a truly disease modifying therapeutic approach.FundingMerck.     

Manipulation of liver regeneration with macrophages to influence the hepatic progenitor cell niche

Insufficient regeneration of the adult liver is believed to cause failure to recover from severe liver disease. An undifferentiated cell population with stem-cell-like qualities known as hepatic progenitor cells (HPCs) is hypothesised to have a central role in regeneration of the adult liver during massive or chronic liver disease. Stem cells in other organ systems are believed to reside in a specialised microenvironment or niche that supports their maintenance and function. The existence of a hepatic stem cell niche might provide a means of therapeutically manipulating endogenous HPCs in vivo as a regenerative therapy.To investigate the physiological potential of HPCs to regenerate the mammalian liver, we have established a novel model of hepatocellular injury and HPC activation using genetic manipulation of hepatocytes. After hepatocyte senescence and death in this model (AhCre Mdm2^flox), HPCs expand and bring about the complete regeneration of the liver parenchyma.We demonstrate that a stereotypical niche, consisting partly of macrophages, exists in both animal models and correlating human disease. Using cell tracking, we show active recruitment of extrahepatic macrophages into this niche during injury. In health, intravenous injection of macrophages results in macrophage engraftment to the liver niche, with subsequent HPC activation and changes to liver structure and function.Within the niche, macrophages use paracrine signalling to control both HPC proliferation and cell fate via TWEAK (tumour-necrosis-factor-like weak inducer of apoptosis) and the Wnt signalling pathway, respectively. After hepatocellular injury, macrophages ingest hepatocyte debris, and release Wnt which promotes HPC differentiation into hepatocytes. TWEAK is vital for HPC proliferation in the AhCre Mdm2^flox model of regeneration. Here, the absence of TWEAK signalling results in liver failure and mortality.This work has demonstrated for the first time the ability of a solid organ to fully regenerate in the adult mammal from progenitor cells, and additionally highlights mechanisms by which this process can be modulated by either small molecule or cell therapy.FundingUniversity of Edinburgh.     

Balancing values and imperatives: a study of nursing service in an ICU.

There has been significant attention from the managers and purchasers of health services regarding the economic advantages that result from changes to the patterns of health care delivery in the acute hospital setting. The impact of these changes, whilst often rendering advantage at the economic management level of health care, can have different consequences for the people who deliver and the people who receive health service. This paper reports on a study that was conducted with a group of nurses to investigate the practice milieu of a critical care unit in the context of changes to health service management. Interpretive methods were used to capture the perspective of the nurses and the way they interpret the multiple factors that influence their practice and their practice environment. The findings indicate that the nurses in the study setting interpret these factors according to the influences they have on the structure, the geography and the value of their work. Explication of these findings provides a research base to inform recommendations relating to improving the practice milieu of the critical care environment.     

Effects of positive end-expiratory pressure on diaphragm function.

Patients admitted to the PACU after surgery may require mechanical ventilation. Knowledge about the anatomy and physiology of the diaphragm and its association with ventilator modes may be helpful in the management of this patient. As the acuity of PACU patients increase, more patients may also be on higher levels of positive end-expiratory pressure (PEEP), requiring PACU nurses to understand the relationship between PEEP and diaphragm function to facilitate weaning. This article provides a review of the mechanical ventilation mode of PEEP and its relationship to diaphragmatic performance. The physiological effects associated with the use of PEEP are also reviewed.     

Length and force of the gastrocnemius and soleus during gait following tendo Achilles lengthenings in children with equinus

Nine subjects (12 sides) with cerebral palsy who walked in equnius were evaluated prior to and 1 year after surgical tendo Achilles lengthening. Gastrocnemius and soleus length [Gait Posture, 6 (1997) 9] and plantarflexor force [Gait Posture, 6 (1997) 9; J Biomech, 23 (1990) 495] were calculated. The length of the gastrocnemius and soleus increased significantly (P<0.01) following the intervention. Force output of the triceps surae during push-off increased significantly (13.95 N/kg body weight (BW) preop to 30.31 N/kg BW postop; P<0.01). Assessment of the force-length capacity of the triceps surae in candidates for tendo Achilles lengthenings may identify individuals at risk of residual weakness and iatrogenic crouch.     

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13–dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.     

肩周炎20例的综合疗效

1 临床资料 2004-04以来收治肩周炎20(男8,女10)例;年龄42～55岁19例,70岁1例;右侧16例,左侧4例;病史7 d～1.5 a,均无外伤史,患侧肩部活动受限,手臂上提小于40°,肩关节外展,外旋活动受限,不能自如穿、脱衣和梳理头发及摸背. 分型与药物组方见表1.     

Changes in central artery blood pressure and wave reflection during a cold pressor test in young adults

The relative contribution of sympathetic nervous system (SNS)-induced increase in peripheral vascular resistance on central artery blood pressure (BP) and aortic wave reflection (augmentation index; AIx) is not completely understood. Central BP and wave reflection characteristics were measured using radial artery applanation tonometry before, during a 3-min cold pressor test (CPT), and 90 and 180-s post-CPT in 15 young, healthy adults (25 +/- 1 years). The CPT resulted in a greater magnitude of change in the estimated aortic systolic (31 vs. 23%, P < 0.05) and pulse (31 vs. 13%, P < 0.05) BP compared with the change in brachial artery BP. Additionally, the CPT resulted in an increased mean arterial pressure (MAP) (P < 0.05) and AIx (10 +/- 2 vs. 26 +/- 2%, P < 0.05). The change in MAP during the CPT was correlated to the change in AIx (r = 0.73, P < 0.01) and inversely related to roundtrip duration of the reflected wave to the periphery and back (r = -0.57, P < 0.05). The present study suggests that cold pressor testing results in a significant increase in arterial wave reflection intensity, possibly due to an increased MAP. However, the greater increase in systolic and pulse BP in the central compared with the peripheral circulation suggests that increased central artery wave reflection intensity contributes to increased left ventricular myocardial oxygen demand during CPT-induced hypertension.