Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169(+) cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL(lpr/lpr) mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.     

Associations between inflammatory markers, candidate polymorphisms and physical performance in older Danish twins

Inflammation may play an essential role in the decline of physical performance. In this study we investigated the associations between inflammatory markers, candidate polymorphisms and physical performance in elderly people. Plasma levels of TNF-α, IL-6, CRP, fibrinogen, sICAM-1 and candidate polymorphisms were measured in 600 twin individuals aged 73 years and older participating in the Longitudinal Study of Aging Danish Twins. Physical performance was assessed using a self-reported measure. The inclusion of twins allowed both traditional and within-twin-pair analysis which permitted control for shared environment and genetic factors. Higher levels of inflammatory markers were generally associated with a lower level of physical performance. The TNFα-238G/A polymorphism was significantly associated with physical performance in men, with A allele carriers having significantly better performance than GG homozygotes. However, this gene variation seems to have only a minor role in explaining the associations between the levels of inflammatory markers and physical performance. When using twin pair analysis to test whether genetic factors in general account for this association, results showed that the association between the level of fibrinogen and physical performance could be caused by genetic factors. Also the association between the level of TNF-α and physical performance in males could be caused by genetic factors. However, other gene variations than the candidate gene polymorphisms studied here seem to explain the major part of the genetic proportion of this association.     

Eosinophil associated genes in the inflammatory bowel disease 4 region: Correlation to inflammatory bowel disease revealed

AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP).METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn’s disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5’-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP^® system as described by the manufacturer. Statistical tests for calculations of results were χ² test, Fisher’s exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant.RESULTS: The genotype frequency for males with UC and with an age of disease onset of ≥ 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject’s genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29%,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of ≥ 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in μg/10⁶ eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes.CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.     

Interest and attitudes of patients,cancer physicians,medical students and cancer researchers towards a spectrum of genetic tests relevant to breast cancer patients

The perspectives of patients and healthcare professionals towards breast cancer genetic tests that are becoming increasingly available is unexplored in Asians. We surveyed the interest and attitudes of 200 breast cancer patients, 67 cancer physicians, 485 medical students and cancer researchers towards three genetic tests, BRCA1/2 mutation, CYP2D6 genotype and Oncotype DX testing, using hypothetical scenarios. Approximately 60% of patients expressed initial interest in each genetic test, although the majority reversed their decisions once test limitations were conveyed, with <15% maintaining interest in each test. Cancer physicians were most likely to recommend BRCA1/2 mutation testing (73%) and least likely to recommend CYP2D6 genotyping (12%), while patients were more likely to choose Oncotype DX testing (28%) over CYP2D6 (21%) and BRCA1/2 testing (15%). Cost concerns, low educational level and lack of prior awareness of genetic testing were the main barriers against breast cancer genetic testing among Asian patients.     

Prediction of evolution toward brain death upon admission to ICU in comatose patients with spontaneous intracerebral hemorrhage using simple signs

The aim of the study was to identify the predictors of brain death (BD) upon admission to the intensive care unit (ICU) of comatose patients with spontaneous intracerebral hemorrhage (ICH). Patients admitted in our ICU from 2002 to 2010 for spontaneous ICH and placed under mechanical ventilation were retrospectively analyzed. Of the 72 patients, 49% evolved to BD, 39% died after withdrawal of life support, and 12% were discharged alive. The most discriminating characteristics to predict BD were included in two models; Model 1 contained ≥3 abolished brainstem responses [adjusted odds ratios (OR) = 8.4 (2.4, 29.1)] and the swirl sign on the baseline CT‐scan [adjusted OR = 5.0 (1.6, 15.9)] and Model 2 addressed the abolition of corneal reflexes [unilateral/bilateral: adjusted OR = 4.2 (0.9, 20.1)/8.8 (2.4, 32.3)] and the swirl sign on the baseline CT‐scan [adjusted OR = 6.2 (1.9, 20.0)]. Two scores predicting BD were created (sensitivity: 0.89 and 0.88, specificity: 0.68 and 0.65). Risk of evolution toward BD was classified as low (corneal reflexes present and no swirl sign), high (≥1 corneal reflexes abolished and swirl sign), and intermediate. Simple signs at ICU admission can predict BD in comatose patients with ICH and could increase the potential for organ donation.     

Single-incision transumbilical levels 1 and 2 axillary lymph node dissection using a flexible endoscope in human cadaveric models

Background

The use of the flexible endoscope as a surgical platform potentially exposes a range of new surgical approaches and benefits yet to be fully defined. A new method using the flexible endoscope to undertake axillary dissection for breast cancer treatment is explored together with an investigation into its acceptability to the general public.

Methods

Endoscopic axillary dissection via a transumbilical approach using the flexible endoscope passed subcutaneously from the umbilicus is described for four human cadaveric axillas. A questionnaire, validated by clinicians, explored the general public’s reaction to the approach and how it might be influenced by potentially serious morbidity such as an increased rate of cancer recurrence.

Results

All axillas were accessed successfully via the transumbilical approach. Levels 1 and 2 axillary dissection was attempted on four axillas. Scarring from previous axillary surgery prevented dissection in one case. In the remaining three cases, respectively 12, 11, and 14 lymph nodes were harvested. The operative times improved with each case, from 1080 to 390 min. A total of 127 people responded to the questionnaire, with 73 % preferring the described approach over the open and periareolar alternatives when morbidities were considered equivalent. When a hypothetical elevated risk of cancer recurrence was included with the transumbilical approach, one-fifth of the public still accepted the approach due to the likelihood of a superior cosmesis.

Conclusion

The use of the flexible endoscope for oncologically safe levels 1 and 2 axillary dissection is possible and would be acceptable to the general public if it were clinically approved. However, significant challenges with the current endoscopic equipment and relevant instrumentation limit the potential of the technique. Technical innovation in terms of new instrument design with improved ergonomics will reduce long operating times and fatigue, thus ensuring surgical acceptance of the flexible endoscope.     

Comment to text by Leif Thuesen, “PCI-The ugly duckling”

Objectives. The aim of the study was to compare extent of coronary disease and subsequent long-term survival in women compared to men adjusted for baseline differences in demographics and morbidity. Design. In the database at Feiring Heart Clinic 18 767 patients had a coronary angiographic examination in the period from March 1999 to December 31, 2006. Their survival status as of May 31, 2007 was ascertained through the Norwegian National Registry. Survival was compared using age stratified analyses and Cox regression adjusting for baseline differences. Results. Significantly more women than men had no coronary disease (28.7 vs. 10.5%, p <0.001), while three vessel disease was more frequently present in men (38.7 vs. 21.8%, p <0.001), as judged by coronary angiography. Covariate adjusted survival was significantly better in women compared to men with an overall hazard ratio of 1.29 (p <0.001), but with no significant difference in the subgroup with high left ventricular end diastolic pressure. Conclusions. At the time of referral to invasive examination women had less extensive coronary artery disease than men as judged by coronary angiography and improved long-term survival when baseline differences were accounted for.