Targeted exome sequencing in anti-factor H antibody negative HUS reveals multiple variations

Background

Genetic susceptibility to atypical hemolytic uremic syndrome (aHUS) may lie within genes regulating or activating the alternate complement and related pathways converging on endothelial cell activation.

Methods

We tested 32 Indian patients of aHUS negative for antibodies to complement factor H for genetic variations in a panel of 15 genes, i.e., CFH, CFHR1-5, CFI, CFB, C3, CD46, MASP2, DGKE, ADAMTS13, THBD and PLG using next-generation DNA sequencing and for copy number variation in CFHR1-3.

Results

Despite absence of a public database of exome variations in the Indian population and limited functional studies, we could establish a genetic diagnosis in 6 (18.8%) patients using a stringent scheme of prioritization. One patient carried a likely pathogenic variation. The number of patients carrying possibly pathogenic variation was as follows: 1 variation: 5 patients, 2 variations: 9 patients, 3 variations: 5 patients, 4 variations: 9 patients, 5 variations: 2 patients and 6 variations: 2 patients. Homozygous deletion of CFHR1-3 was present in five patients; none of these carried a diagnostic genetic variation. Patients with or without diagnostic variation did not differ significantly in terms of enrichment of genetic variations that were rare/novel or predicted deleterious, or for possible environmental triggers.

Conclusion

We conclude that genetic testing for multiple genes in patients with aHUS negative for anti-FH antibodies reveals multiple candidate variations that require prioritization. Population data on variation frequency of the Indian population and supportive functional studies are likely to improve diagnostic yield.

     

Evolving approach to the varicocele

The varicocele is the most common cause of male infertility world wide. Varicoceles have been found in 15% of the normal male population and in up to 40% of patients with male infertility. In approximately 70% of patients with secondary infertility, a varicocele is an underlying cause. Understanding of the pathophysiology, treatments, and outcomes of a varicocele and varicocele repair has evolved significantly over the past several decades. Our goal is to discuss the approach to its diagnosis and treatment that has evolved.     

Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study)

Circulating osteoprotegerin (OPG) has been shown to be elevated in patients with vascular disease. The role of OPG as a biomarker for atherosclerosis in a large, unselected population is not well known. Plasma OPG levels were measured in 3,386 subjects in the Dallas Heart Study, a multiethnic, population-based probability sample of adults aged 30 to 65 years. Coronary artery calcium (CAC) was measured by electron beam computed tomography. Aortic plaque was assessed by magnetic resonance imaging. Multivariable logistic regression was used to assess associations among OPG, cardiovascular risk factors, CAC, and aortic plaque. Age, female gender, black race, smoking, personal and family history of coronary artery disease (CAD), diabetes mellitus, hyperlipidemia, CAC, and aortic plaque were significantly associated with higher plasma OPG levels (p <0.01) in univariable analyses. The prevalence of CAC and aortic plaque increased across OPG quartiles (p <0.001 for each). An OPG level in the fourth quartile was independently associated with CAC (RR 1.39, 95% confidence interval 1.01 to 1.93) and aortic plaque (RR 1.42, 95% confidence interval 1.09 to 1.86) after adjustment for age, gender, smoking, diabetes, hyperlipidemia, and family history of premature CAD. In conclusion, plasma OPG is independently associated with CAC and aortic plaque in an unselected population, suggesting it may be a novel biomarker for atherosclerosis in humans.     

A study on the biosorption kinetics of Cu (II) and Zn (II) ions from aqueous phase (sulphate medium) using waste sawdust generated from Acacia nilotica wood carpentry

Ecotoxicology - In the present study, the natural biosorption capacity of Acacia nilotica sawdust (wood biomass) was studied for the removal of copper (Cu) and zinc (Zn) heavy metal ions. The...     

Incisional, epigastric and umbilical hernia repair using the Prolene Hernia System: describing a novel technique

The Prolene Hernia System (PHS) is already widely in use in the United Kingdom for inguinal hernias. We describe the novel technique of using the three-in-one design of the PHS (Ethicon Endo-Surgery, Bracknell, UK) for repairing incisional, epigastric and umbilical herniae. This is a three-dimensional device and consists of an onlay patch, a tubular connector and an underlay patch. We recommend a four ‘corner’ suturing of the underlay patch under vision (and then) through the full thickness of abdominal wall layers to ensure a flat underlay mesh. These four sutures flatten out the underlay patch and can be tied or removed with equal effect. The sutures are placed at 3, 6, 9 and 12 o’clock, which simplifies the procedure and ensures that the underlay lays correctly and is corrugation-free and tension-free, thereby providing a two-layer repair for those herniae with a high rate of recurrence. Both authors are independent surgeons who have no conflicts of interest with Ethicon Endo-Surgery. This report has not been published elsewhere; the information contained in it has recently been presented as a poster at the National Hernia Symposium in Birmingham, UK, 8 February 2006.     

Agreement between methods of measurement of mean aortic wall thickness by MRI

Purpose

To assess the agreement between three methods of calculation of mean aortic wall thickness (MAWT) using magnetic resonance imaging (MRI).

Materials and Methods

High‐resolution MRI of the infrarenal abdominal aorta was performed on 70 subjects with a history of coronary artery disease who were part of a multi‐ethnic population‐based sample. MAWT was calculated as the mean distance between the adventitial and luminal aortic boundaries using three different methods: average distance at four standard positions (AWT‐4P), average distance at 100 automated positions (AWT‐100P), and using a mathematical computation derived from the total vessel and luminal areas (AWT‐VA). Bland‐Altman plots and Passing‐Bablok regression analyses were used to assess agreement between methods.

Results

Bland‐Altman analyses demonstrated a positive bias of 3.02 ± 7.31% between the AWT‐VA and the AWT‐4P methods, and of 1.76 ± 6.82% between the AWT‐100P and the AWT‐4P methods. Passing‐Bablok regression analyses demonstrated constant bias between the AWT‐4P method and the other two methods. Proportional bias was, however, not evident among the three methods.

Conclusion

MRI methods of measurement of MAWT using a limited number of positions of the aortic wall systematically underestimate the MAWT value compared with the method that calculates MAWT from the vessel areas. J. Magn. Reson. Imaging 2009;29:576–582. © 2009 Wiley‐Liss, Inc.