Prognostic value of cardiovascular MR imaging biomarkers on outcome in peripheral arterial disease: a 6-year follow-up pilot study

The objective of this pilot study was to explore the prognostic value of outcome of cardiovascular magnetic resonance (MR) imaging biomarkers in patients with symptomatic peripheral arterial disease (PAD) in comparison with traditional risk factors. Forty-two consecutive patients (mean age 64?±?11 years, 22 men) referred for contrast-enhanced MR angiography (CE-MRA) were included. At baseline a comprehensive cardiovascular MRI examination was performed: CE-MRA of the infra-renal aorta and run-off vessels, carotid vessel wall imaging, cardiac cine imaging and aortic pulse wave velocity (PWV) assessment. Patients were categorized for outcome at 72?±?5 months follow-up. One patient was lost to follow-up. Over 6 years, six patients had died (mortality rate 14.6?%), six patients (14.6?%) had experienced a cardiac event and three patients (7.3?%) a cerebral event. The mean MRA stenosis class (i.e., average stenosis severity visually scored over 27 standardized segments) was a significant independent predictor for all-cause mortality (beta 3.0?±?standard error 1.3, p?=?0.02). Descending aorta PWV, age and diabetes mellitus were interrelated with stenosis severity but none of these were significant independent predictors. For cardiac morbidity, left ventricular ejection fraction (LVEF) and mean MRA stenosis class were associated, but only LVEF was a significant independent predictor (beta ?0.14?±?0.05, p?=?0.005). Diabetes mellitus was a significant independent predictor for cerebral morbidity (beta 2.8?±?1.3, p?=?0.03). Significant independent predictors for outcome in PAD are mean MRA stenosis class for all-cause mortality, LVEF for cardiac morbidity and diabetes mellitus for cerebral morbidity.     

Site-specific association between distal aortic pulse wave velocity and peripheral arterial stenosis severity: a prospective cardiovascular magnetic resonance study

Background

Vascular disease expression in one location may not be representative for disease severity in other vascular territories, however, strong correlation between disease expression and severity within the same vascular segment may be expected. Therefore, we hypothesized that aortic stiffening is more strongly associated with disease expression in a vascular territory directly linked to that aortic segment rather than in a more remote segment. We prospectively compared the association between aortic wall stiffness, expressed by pulse wave velocity (PWV), sampled in the distal aorta, with the severity of peripheral arterial occlusive disease (PAOD) as compared to atherosclerotic markers sampled in remote vascular territories such as PWV in the proximal aorta and the normalized wall index (NWI), representing the vessel wall thickness, of the left common carotid artery.

Methods

Forty-two patients (23 men; mean age 64±10 years) underwent velocity-encoded cardiovascular magnetic resonance (CMR) in the proximal and distal aorta, whole-body contrast-enhanced MR angiography (CE-MRA) and carotid vessel wall imaging with black-blood CMR in the work-up for PAOD. Strength of associations between aortic stiffness, carotid NWI and peripheral vascular stenosis grade were assessed and evaluated with multiple linear regression.

Results

Stenosis severity correlated well with PWV in the distal aorta (Pearson r_P=0.64, p<0.001, Spearman r_S=0.65, p<0.001) but to a lesser extent with PWV in the proximal aorta (r_P=0.48, p=0.002, r_S=0.22, p=0.18). Carotid NWI was not associated with peripheral stenosis severity (r_P=0.17, p=0.28, r_S=0.14, p=0.37) nor with PWV in the proximal aorta (r_P=0.22, p=0.17) nor in the distal aorta (r_P=0.21, p=0.18). Correlation between stenosis severity and distal aortic PWV remained statistically significant after correction for age and gender.

Conclusions

Distal aortic wall stiffness is more directly related to peripheral arterial stenosis severity than markers from more remote vascular territories such as proximal aortic wall stiffness or carotid arterial wall thickness. Site-specific evaluation of vascular disease may be required for full vascular risk estimation.     

Improving global monitoring of vaccine safety: a survey of national centres participating in the WHO Programme for International Drug Monitoring.

BACKGROUND: The WHO Programme for International Drug Monitoring (PIDM) was established in 1968 following the thalidomide disaster. The PIDM has had considerable success in analyzing drug-related adverse event reports, but more limited progress has been made in analyzing vaccine-related reports. In June 2005, the Global Advisory Committee on Vaccine Safety, acknowledging these limitations, called for a global consultation to address the need for improved monitoring and analysis of vaccine-related adverse event reports on an international level. OBJECTIVE: In preparation for this consultation and as part of a larger study designed to evaluate the PIDM, a survey of the National Pharmacovigilance Centres of all 76 countries participating in the PIDM at the time the survey was conducted. RESULTS: Thirty-six countries (47%) responded. Of the 36 responding countries, 16 (44%) reported having a separate surveillance system for adverse events following immunizations (AEFIs) and 30 (83%) reported forwarding AEFI reports to the PIDM. Seven of the 36 countries (19%) indicated that one or more population subgroups are systematically excluded from their country's AEFI surveillance system. Five of the seven countries exclude reports concerning recipients of travellers' vaccines; three exclude recipients of vaccines administered by private physicians outside the national immunization programme and supply scheme; and five exclude reports from the military sector. Only half of the respondents knew of the Brighton Collaboration, a major international initiative aimed at the standardization of AEFI definitions. CONCLUSION: The survey identified critical elements that should be addressed quickly to improve global vaccine safety monitoring. Communication between national adverse drug reaction and AEFI surveillance authorities, ability to pay for advancing technology in developing countries, and proper use of services and terminologies are issues of concern.     

Patient and tumor characteristics of bilateral breast cancer at screening mammography in the Netherlands, a population-based study

Few data are available on bilateral breast cancer in the screening population. The aim of this study was to determine patient and tumor characteristics of women with bilateral breast cancer at screening mammography. We included all 350,637 screening mammography examinations of women participating in a biennial screening program in a southern screening region of the Netherlands between May 1998 and January 2010. For referred women, all breast imaging reports, biopsy results, and surgery reports during one year after referral were collected. We compared patient and tumor characteristics of referred women with a diagnosis of bilateral breast cancer or unilateral breast cancer at workup. Bilateral or unilateral breast cancer had been diagnosed in respectively 40 (2.2%) and 1766 (97.8%) of 1806 referred women. Women with bilateral or unilateral breast cancer did not differ significantly in mean age, mammographic breast density, family history of breast cancer, or use of hormone replacement therapy. Compared with index cancers, contralateral cancers comprised significantly more lobular cancers (P = 0.02). Tumor size, mitotic activity, and estrogen receptor status were comparable for both groups, but contralateral cancers had a significantly lower risk of lymph node metastases (P = 0.03). Compared to unilateral breast cancer, contralateral malignancies in women with bilateral breast cancer comprised significantly more lobular cancers (P = 0.004) and lymph node negative cancers (P = 0.01). Contralateral breast cancers detected at screening comprise more lobular cancers and show less nodal involvement than index cancers or unilateral cancers. No differences are observed with respect to other patient and tumor characteristics.     

Improving global monitoring of vaccine safety: a quantitative analysis of adverse event reports in the WHO Adverse Reactions Database

The World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) was initially developed for chemical rather than biological products. The PIDM made considerable achievements in analysing drug-related adverse event reports, progress was more limited for vaccine-related reports. In 2005, the Global Advisory Committee on Vaccine Safety, called for a global consultation to address the need for improved monitoring and analysis of vaccine-related adverse event reports on an international level. In preparation for this consultation, the WHO Adverse Reactions Database was quantitatively assessed and results of this analysis are presented in this paper. Three countries contributed 82% of vaccine-related reports in the database. The mean difference between onset date and report date was 2.4 years. Several issues of concern were identified, such as the fact that many member countries do not forward any or all reports of adverse events following immunization to the PIDM, and the poor timeliness and regularity of reporting, which could prevent timely generation of safety signals.     

Malpractice claims following screening mammography in The Netherlands

Although malpractice lawsuits are frequently related to a delayed breast cancer diagnosis in symptomatic patients, information on claims at European screening mammography programs is lacking. We determined the type and frequency of malpractice claims at a Dutch breast cancer screening region. We included all 85,274 women (351,009 screens) who underwent biennial screening mammography at a southern breast screening region in The Netherlands between 1997 and 2009. Two screening radiologists reviewed the screening mammograms of all screen detected cancers and interval cancers and determined whether the cancer had been missed at the previous screen or at the latest screen, respectively. We analyzed all correspondence between the screening organization, clinicians and screened women, and collected complaints and claims until September 2011. At review, 20.9% (308/1,475) of screen detected cancers and 24.3% (163/670) of interval cancers were considered to be missed at a previous screen. A total of 19 women (of which 2, 6 and 11 women had been screened between 1997 and 2001 (102,439 screens), 2001 and 2005 (114,740 screens) and 2005 and 2009 (133,830 screens), respectively) had contacted the screening organization for additional information about their screen detected cancer or interval cancer, but filed no claim. Three other women directly initiated an insurance claim for financial compensation of their interval cancer without previously having contacted the screening organization. We conclude that screening-related claims were rarely encountered, although many screen detected cancers and interval cancers had been missed at a previous screen. A small but increasing proportion of women sought additional information about their breast cancer from the screening organization.     

Clinical Variability of Family Members with the C104R Mutation in Transmembrane Activator and Calcium Modulator and Cyclophilin Ligand Interactor (TACI)

Purpose

Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. The C104R mutation in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is the most frequent mutation identified in patients with CVID. We carried out a detailed immunological and molecular study in a family with a C104R mutation.

Methods

We have undertaken segregation analysis of a kindred with C104R mutations of the TACI gene. Detailed immunological and molecular investigations were carried out for this kindred and the clinical phenotype was compared to the genotype.

Results

Segregation analysis of our kindred showed that inheriting single or double copy of the C104R mutation does not consign an individual to CVID. All heterozygotes in the family were phenotypically different, ranging from asymptomatic to ill-health. A family member with a wild type TACI variant had CVID-related phenotype including IgA deficiency and type 1 diabetes. Interestingly, a family member with the homozygous C104R/C104R variant did not meet the criteria for CVID because he had excellent, albeit unsustained, vaccine responses to T cell dependent and T cell independent vaccine antigens despite profound hypogammaglobulinemia.

Conclusion

The C104R mutation does not correlate with the clinical phenotypes in this family.     

Identification of Germinal Centres in the Lymph Node of a Patient with Hyperimmunoglobulin M Syndrome Associated with Congenital Rubella

Background

The hyper immunoglobulin M syndrome (HIM) associated with congenital rubella infection (rHIM) is an extremely rare disorder, where patients have elevated serum IgM in association with reduced IgG and IgA. We have previously shown that in contrast to X-linked HIM (XHIM), a patient with well-characterised rHIM is able to express functional CD40 ligand, undergo immunoglobulin isotype switching and to generate memory B cells. Here we describe the ultrastructural features of an excised lymph node from this patient.

Methods

An inguinal lymph node was surgically removed and examined histologically as well as by immunohistochemistry. It was then stained with multiple fluorescent dyes to visualize the cellular interactions within the node. Flow cytometry was undertaken on a cellular suspension from the node.

Findings

Our patient has normal lymph node architecture by light microscopy. Immunohistochemistry studies showed the presence of scattered germinal centres. Polychromatic immunofluorescence staining showed disruption of the architecture with mostly abnormal germinal centres. A small number of relatively intact germinal centres were identified. Both IgM and IgG bearing cells were identified in germinal centres.

Interpretation

In contrast to XHIM where germinal centres are absent, the presence of small numbers of relatively normal germinal centres explain our previous identification of isotype switched memory B cells in rHIM.