Radiographic damage associated with low bone mineral density and vertebral deformities in rheumatoid arthritis: The Oslo‐Truro‐Amsterdam (OSTRA) collaborative study

Objective

To examine variables associated with bone mineral density (BMD) and vertebral deformities in women with rheumatoid arthritis (RA) from 3 northwest European countries.

Methods

Female patients were recruited from rheumatology clinics in Oslo, Norway; Truro, UK; and Amsterdam, The Netherlands (150 total, 50 per center, age 50–70 years, disease duration ≥5 years). Demographic and clinical data were collected and BMD was measured by means of dual energy x‐ray absorptiometry. Associations between demographic and clinical measures on the one hand and BMD and vertebral deformities on the other were investigated by single and multiple regression analyses.

Results

Body mass index (BMI), medication use, RA damage measures, and BMD differed significantly between the 3 centers. Overall, Norwegian patients had the lowest BMI, used more corticosteroids and antiosteoporotic drugs, had lower joint damage measured by Larsen score, and lower BMD at both spine and hip. High age, low BMI, and high cumulative dose of corticosteroids (last 2 years) are related to low BMD. A high Larsen score was associated with low BMD at the hip. Larsen score was the independent determinant of vertebral deformities after correction for center, age, BMI, and BMD.

Conclusion

Data from 3 countries on BMD and vertebral deformities in female patients aged 50–70 years with longstanding RA are presented, demonstrating an association between radiographic RA damage and low BMD and between radiographic RA damage and vertebral deformities.

     

Homografts in patients with combined disease of the aortic valve and the ascending aorta: an alternative to the classical Bentall procedure

BACKGROUND AND AIM OF THE STUDY: In patients with aneurysms or dissections of the ascending aorta and additional aortic valve disease, valve-containing composite grafts are used in clinical routine. The study aim was to present our experience with homografts for aortic valve replacement extended by a vascular prosthesis as an alternative to the classical Bentall procedure. METHODS: Thirty consecutive patients (mean age 46+/-14 years) were included in this study. Indications for valve replacement were aortic stenosis (n = 15), aortic insufficiency (n = 6), combined aortic valve disease (n = 6), endocarditis of the native valve (n = 1), and endocarditis of a previously placed bioprosthesis (n = 2). The mean diameter of the ascending aorta was 5.6+/-0.5 cm; one patient had an acute dissection (diameter 4.4 cm). For valve replacement, cryopreserved homografts (mean size 24+/-2 mm) were used in a mini-root technique, and the ascending aorta was replaced by collagen-coated vascular prostheses (mean diameter 28+/-3 mm). The size of the vascular prosthesis was adjusted to the diameter of the sinutubular junction of the implanted homograft. Follow up included annual clinical examinations, transthoracic echocardiography and ultrafast computed tomography (CT) scans. RESULTS: All patients survived surgery, and no deaths occurred during follow up. None of the patients had postoperative anticoagulation, and no thromboembolic events were noted. Follow up was complete, with an average 48 months (range: 6 to 84 months). Doppler echocardiography revealed trivial to mild aortic regurgitation in nine patients postoperatively, with no deterioration during follow up. No pathologic pressure gradients over the aortic valves were measured at Doppler echocardiography; the mean valvular orifice area was 2.5+/-0.3 cm2. At ultrafast CT, normal homograft anatomy including the sinotubular junction, no calcifications, and no signs of annular dilatation were seen. In the patient who had surgery for acute endocarditis of the native valve, ultrafast CT revealed a small pseudoaneurysm below the left coronary artery, without need for reoperation. CONCLUSION: Short- and mid-term results show that cryopreserved homografts extended by small-sized vascular prostheses can be used safely for Bentall procedures in selected cases where the diameter of the aortic valve annulus is moderately dilated.     

Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion‐positive prostate cancers

Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1‐specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG⁺ cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG⁺ tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG⁺ cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over‐expression of FOXP1, RYBP and SHQ1 resulted in decreased colony‐formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG⁺ prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The diagnosis and management of allergic reactions in patients sensitized to non-specific lipid transfer proteins

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.     

A monoclonal antibody against an activation epitope on mouse integrin chain beta 1 blocks adhesion of lymphocytes to the endothelial integrin alpha 6 beta 1.

We have generated a monoclonal antibody (mAb), 9EG7, against mouse endothelial cells that blocks adhesion of lymphocytes to endothelial cells. Sequencing of four tryptic peptides of the purified antigen revealed its identity with the integrin chain beta 1. The only beta 1 integrin that is known to mediate cell-cell adhesion is alpha 4 beta 1 (VLA-4). This is not the integrin that is functionally defined by the mAb 9EG7 on endothelial cells. First, alpha 4 is not present on the analyzed endothelial cells. Second, mAb 9EG7 does not block the cell-adhesion function of alpha 4 beta 1 on the nonactivated mouse lymphoma L1-2. Thus, the mAb 9EG7 can functionally distinguish between different beta 1 integrins and defines a beta 1 integrin other than alpha 4 beta 1 as a newly discovered cell-cell adhesion molecule. This integrin is most likely alpha 6 beta 1, since an antibody against the alpha 6 chain blocks lymphocyte adhesion to the same degree as the mAb 9EG7, the effect of both antibodies is not additive, and the alpha 6 chain is coprecipitated with beta 1 in 9EG7 immunoprecipitations. Surprisingly, activation of alpha 4 beta 1 on L1-2 cells with phorbol ester or Mn2+ allows blocking of alpha 4 beta 1-mediated adhesion of L1-2 cells to endothelial cells with mAb 9EG7. Furthermore, only the activated alpha 4 beta 1 heterodimer, but not the unactivated complex, is detectable with 9EG7 in immunoprecipitations and by flow cytometry. Thus, mAb 9EG7 defines an epitope on integrin chain beta 1, which is accessible on the alpha 4 beta 1 heterodimer only after activation of this integrin.     

The Premonitory Phase of Migraine – What Can We Learn From It?

This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using PubMed for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7‐88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain.