Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population

BACKGROUND: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. METHODS: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype-phenotype relationships were also sought. Meta-analysis was conducted via RevMan. RESULTS: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). CONCLUSIONS: TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes.     

Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia

Primary cilia are ubiquitous cellular appendages that provide important yet not well understood sensory and signaling functions. Ciliary dysfunction underlies numerous human genetic disorders. However, the precise defects in cilia function and the basis of disease pathophysiology remain unclear. Here, we report that the proteins disrupted in the human ciliary disorder Bardet-Biedl syndrome (BBS) are required for the localization of G protein-coupled receptors to primary cilia on central neurons. We demonstrate a lack of ciliary localization of somatostatin receptor type 3 (Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1) in neurons from mice lacking the Bbs2 or Bbs4 gene. Because Mchr1 is involved in the regulation of feeding behavior and BBS is associated with hyperphagia-induced obesity, our results suggest that altered signaling caused by mislocalization of ciliary signaling proteins underlies the BBS phenotypes. Our results also provide a potential molecular mechanism to link cilia defects with obesity.     

Comparative effects of sevoflurane and propofol based general anaesthesia for elective surgery on memory

Introduction

Unconscious processing of words during general anaesthesia has been suggested. We used the process dissociation procedure (PDP) to test memory performance during sevoflurane and propofol anaesthesia in relation to hypnotic depth.

Material and methods

One hundred participants anaesthetised for elective surgery (50 with propofol and 50 with sevoflurane) and 50 non-anaesthetized listened to a list of words. The bispectral index (BIS) of the anaesthetised patients was recorded. Within 36 h after word presentation, memory was assessed using a word stem completion task, based on Buchner''s model applied on the PDP.

Results

There was evidence of memory for words presented during light (BIS 61-80) (p = 0.001) and adequate (BIS 41-60) (p = 0.008) but not deep anaesthesia (BIS 21-40) (p = 0.09). The PDP showed a significant implicit but not explicit memory contribution (mean total explicit memory scores: 0.04 ±0.07 in all BIS categories; mean implicit memory scores: 0.01 ±0.04, 0.1 ±0.08, and 0.05 ±0.09 at BIS = 21-40, 41-60, and 61-80, respectively). There was a statistically significant difference between the mean implicit memory score (I) of the propofol and sevoflurane group in the BIS category 41-60 in general (p = 0.016), and after incision (I_A.I.) (p = 0.005) in particular, with propofol depressing I more than sevoflurane in both cases. Memory performance of nonanaesthetized participants was better, with a higher contribution of explicit and a comparable contribution of implicit memory.

Conclusions

During general anaesthesia, implicit memory persists even in adequate hypnotic states. Sevoflurane affects the implicit memory of adequately anaesthetised subjects less than propofol.     

A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.     

Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis

Thrombomodulin is a cell surface-expressed glycoprotein that serves as a cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell PC receptor. The PC pathway is a major anticoagulant mechanism that downregulates thrombin formation and hedges thrombus formation. The objectives of this review were to review recent findings regarding thrombomodulin structure, its involvement in the regulation of hemostasis and further discuss the implication, if any, of the genetic polymorphisms in the thrombomodulin gene in the risk of development of thrombosis. We performed a literature search by using electronic bibliographic databases. Although the direct evaluation of risk situations associated with thrombomodulin mutations/polymorphisms could be of clinical significance, it appears that mutations that affect the function of thrombomodulin are rarely associated with venous thromboembolism. However, several polymorphisms are reported to be associated with increased risk for arterial thrombosis. Additionally studies on knock out mice as well studies on humans bearing rare mutations suggest that thrombomodulin dysfunction may be implicated in the pathogenesis of myocardial infraction.