Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress

Background and purpose:

Inflammation is associated with oxidative stress and local generation of lipid peroxidation-derived aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). In most tissues, HNE is readily conjugated with glutathione and presently it is unknown whether glutathionyl-HNE (GS-HNE) plays a functional role in inflammation. Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1).

Experimental approach:

GS-HNE was administered intraperitoneally to mice and peritoneal lavages were assessed for leukocyte infiltration and lipid mediators were targeted by mediator-lipidomics. RvD1 was administered to mice treated with GS-HNE and leukocyte infiltration was assessed in the peritoneum. Superoxide production and CD11b modulation were measured in isolated human polymorphonuclear leukocytes incubated with GS-HNE.

Key results:

GS-HNE (1–10 µg) evoked infiltration of Gr-1⁺ leukocytes into the peritoneum to form an inflammatory exudate. With isolated human polymorphonuclear leukocytes, GS-HNE stimulated both superoxide generation and CD11b expression. Among the lipid mediators, both cyclooxygenase- and lipoxygenase-derived pro-inflammatory eicosanoids, including prostaglandin E₂, leukotriene B₄ and cysteinyl leukotrienes, were generated in exudates of mice injected intraperitoneally with GS-HNE. RvD1, given i.v. in doses as low as 0.01–10.0 ng, sharply reduced GS-HNE-stimulated leukocyte infiltration (∼30–70%).

Conclusions and implications:

Glutathione conjugates of HNE, derived during oxidative stress, are pro-inflammatory in vivo. RvD1 protects against this oxidative stress-initiated inflammation.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

海洋天然产物的药物开发

从海洋天然产物中发现药物近年来再次引起广泛关注。2004年12月,美国FDA批准了第1个源自海洋生物的止痛药齐考诺肽（ziconotide,Prialt）,用于治疗疼痛。2007年10月欧盟了第1个抗癌海洋药物海鞘素（ecteinascidin,Yondelis）。本文将举例说明影响药物发现的因素和要完成一种化合物从海洋到临床试验的飞跃会遇到的各种困难,展望未来,分析海洋药物的乐观前景。     

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.     

Neonatology in the 'Pearl of the East'

ABSTRACT Clinicians practising in different regions of the world are often impressed at marked differences in disease patterns witnessed. The bases of most obvious differences are usually socio-economic and genetic, but culture and environment can be equally important. Documenting and assessing such differences is more than just a passing interest. Globalization has resulted in significant movement of people from one area to another. During the past decade, many young Chinese families have emmigratad to Australia, Europe and North America for social and political reasons. Clinicians in these regions will need to be aware of the 'Chinese disease patterns'. The overview highlights some of the more striking differences seen in neonatal medicine between the East (Hong Kong) and the West (Australia/Europe/North America). In addition to the immediate clinical relevance, it is hoped that this review can provide a background from which fruitful research ideas may emerge and to stimulate interest for trainee neonatologists who wish to seek sabbatical experience in Hong Kong.     

The E rosette-associated antigen of T cells can be identified on blasts from patients with acute myeloblastic leukemia

Monoclonal antibody T-11, considered specific for the sheep erythrocyte rosette-associated antigen of T cells, reacted with leukemic blasts from four of 23 patients with morphologic and cytochemical criteria for acute myeloblastic leukemia (AML). Although 83%, 87%, 88%, and 96% of the blasts from these patients reacted with T-11, only one patient demonstrated a small percentage of heat-stable E rosettes (5%). Antibody 9.6, which also reacts with the E rosette-associated antigen, was tested on blasts from two of the T-11-positive patients and was also strongly reactive (96% and 98%). Dual staining of blasts from these two patients demonstrated a small number of cells that simultaneously expressed the E rosette-associated antigen and myeloid- associated cytochemistries (myeloperoxidase [MPO] and Sudan black B). Additionally, leukemic blasts were identified that simultaneously expressed the E rosette-associated antigen and contained Auer rods. Antibody OKT-11 immunoprecipitated a 48,100-dalton glycoprotein from these leukemic blasts that is similar in molecular weight to that previously determined for the T cell surface protein (Tp50), thus providing strong evidence that this molecule can be found in some cases of AML. Because cells simultaneously expressing both the E rosette- associated antigen and MPO were identified, it would appear likely that leukemic blasts with only the E rosette-associated antigen or only MPO arose from the same progenitor. Our findings further demonstrate that the epitopes identified by antibodies OKT-11, T-11, and 9.6 are not always associated with, or sufficient for, 37 degrees C E rosette formation and can be found on blasts from patients with AML.     

Secular changes in height,weight and body mass index in Hong Kong Children

Background  

Large population growth surveys of children and adolescents aged 6 to 18 y were undertaken in Hong Kong in 1963 and 1993. The global epidemic of obesity is a major public health concern. To monitor the impact of this epidemic in Hong Kong children and to identify secular changes in growth, a further growth survey was undertaken in 2005/6.     

Cost-effectiveness of collaborative care including PST and an antidepressant treatment algorithm for the treatment of major depressive disorder in primary care; a randomised clinical trial

Background  

Depressive disorder is currently one of the most burdensome disorders worldwide. Evidence-based treatments for depressive disorder are already available, but these are used insufficiently, and with less positive results than possible. Earlier research in the USA has shown good results in the treatment of depressive disorder based on a collaborative care approach with Problem Solving Treatment and an antidepressant treatment algorithm, and research in the UK has also shown good results with Problem Solving Treatment. These treatment strategies may also work very well in the Netherlands too, even though health care systems differ between countries.     

Effects of blood transfusion on left ventricular output in premature babies

Objective:   To investigate the acute effects of red blood cell transfusion on haemodynamics in preterm babies.
Setting:   A neonatal unit in a University Hospital.
Patients:   Preterm babies whose postnatal age was less than four weeks and who required red blood cell transfusion.
Measurement:   Cardiac output and left ventricular systolic function was determined using Doppler echocardiography before, one hour and 24  h after red blood cell transfusion. Blood pressure and haematocrit were also recorded at the same time. Mixed-effects regression model was used to analyse the effect of blood transfusion on left ventricular function and cardiac output.
Results:   57 preterm babies were recruited. Univariate analysis showed that cardiac index decreased significantly 24  h after transfusion ( P <0.05). Systemic red cell transport increased by an average of 11.1% 24  h after transfusion ( P <0.05). Multivariate analysis showed that the cardiac index was negatively associated with haematocrit and the index was higher in male babies.
Conclusion:   There was a significant drop in cardiac index and an increase in systemic red cell transport 24  h after transfusion in premature babies.