Dominik Paul

Persistent HIV antigenaemia and decline of HIV core antibodies associated with transition to AIDS.

Sequential serum samples from 13 homosexual men who seroconverted for antibodies to human immunodeficiency virus (HIV) were tested for HIV antigen. In one of these men, who developed the acquired immune deficiency syndrome (AIDS), HIV antigenaemia preceded the onset of AIDS by more than a year and persisted throughout the course of the disease. This antigenaemia was accompanied by the disappearance of IgG antibody reactivity to the major HIV core protein p24. In none of the 12 others, who all remained without serious disease, were serum concentrations of HIV antigen detected, except on one occasion in one man. All their serum samples showed strong IgG antibody reactivity to p24. Nine children who were infected with HIV in 1981 by plasma transfusion from a single donor were also followed up for HIV antigenaemia. HIV antigen was almost constantly present in the serum (26 of 28 samples) of five children who developed AIDS related complex or AIDS and less often in the serum (four of 10 samples) of four children who remained free of symptoms. The two children who developed AIDS showed a virtual absence of antibody reactivity to p24. These results indicate that increased HIV gene expression is a contributing factor to the development of AIDS and also provide evidence for a switch from latent to active HIV infection.

Magnetic Resonance Imaging Contrast Agent Targeted Toward Activated Platelets Allows In Vivo Detection of Thrombosis and Monitoring of Thrombolysis

Background— Platelets are the key to thrombus formation and play a role in the development of atherosclerosis. Noninvasive imaging of activated platelets would be of great clinical interest. Here, we evaluate the ability of a magnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIOs) and a single-chain antibody targeting ligand-induced binding sites (LIBS) on activated glycoprotein IIb/IIIa to image carotid artery thrombi and atherosclerotic plaques. Methods and Results— Anti-LIBS antibody or control antibody was conjugated to 1-&mgr;m MPIOs (LIBS MPIO/control MPIO). Nonocclusive mural thrombi were induced in mice with 6% ferric chloride. MRI (at 9.4 T) was performed once before and repeatedly in 12-minute-long sequences after LIBS MPIO/control MPIO injection. After 36 minutes, a significant signal void, corresponding to MPIO accumulation, was observed with LIBS MPIOs but not control MPIOs (P<0.05). After thrombolysis, in LIBS MPIO–injected mice, the signal void subsided, indicating successful thrombolysis. On histology, the MPIO content of the thrombus, as well as thrombus size, correlated significantly with LIBS MPIO–induced signal void (both P<0.01). After ex vivo incubation of symptomatic human carotid plaques, MRI and histology confirmed binding to areas of platelet adhesion/aggregation for LIBS MPIOs but not for control MPIOs. Conclusions— LIBS MPIOs allow in vivo MRI of activated platelets with excellent contrast properties and monitoring of thrombolytic therapy. Furthermore, activated platelets were detected on the surface of symptomatic human carotid plaques by ex vivo MRI. This approach represents a novel noninvasive technique allowing the detection and quantification of platelet-containing thrombi.

Cartilage Quality Assessment by Using Glycosaminoglycan Chemical Exchange Saturation Transfer and 23Na MR Imaging at 7 T

PURPOSE To compare a glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging method, which enables sampling of the water signal as a function of the presaturation offset (z-spectrum) at 13 points in clinically feasible imaging times, with sodium 23 ((23)Na) magnetic resonance (MR) imaging in patients after cartilage repair surgery (matrix-associated autologous chondrocyte transplantation and microfracture therapy). MATERIALS AND METHODS One female patient (67.3 years), and 11 male patients (median age, 28.8 years; interquartile range [IQR], 24.6-32.3 years) were examined with a 7-T whole-body system, with approval of the local ethics committee after written informed consent was obtained. A modified three-dimensional gradient-echo sequence and a 28-channel knee coil were used for gagCEST imaging. (23)Na imaging was performed with a circularly polarized knee coil by using a modified gradient-echo sequence. Statistical analysis of differences and Spearman correlation were applied. RESULTS The median of asymmetries in gagCEST z-spectra summed over all offsets from 0 to 1.3 ppm was 7.99% (IQR, 6.33%-8.79%) in native cartilage and 5.13% (IQR, 2.64%-6.34%) in repair tissue. A strong correlation (r = 0.701; 95% confidence interval: 0.21, 0.91) was found between ratios of signal intensity from native cartilage to signal intensity from repair tissue obtained with gagCEST or (23)Na imaging. The median of dimensionless ratios between native cartilage and repair tissue was 1.28 (IQR, 1.20-1.58) for gagCEST and 1.26 (IQR, 1.21-1.48) for (23)Na MR imaging. CONCLUSION The high correlation between the introduced gagCEST method and (23)Na imaging implies that gagCEST is a potentially useful biomarker for glycosaminoglycans.

A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy

Dystrophic epidermolysis bullosa (DEB) is a severe skin fragility disorder associated with trauma-induced blistering, progressive soft tissue scarring, and increased risk of skin cancer. DEB is caused by mutations in type VII collagen. In this study, we describe the generation of a collagen VII hypomorphic mouse that serves as an immunocompetent animal model for DEB. These mice expressed collagen VII at about 10% of normal levels, and their phenotype closely resembled characteristics of severe human DEB, including mucocutaneous blistering, nail dystrophy, and mitten deformities of the extremities. The oral blistering experienced by these mice resulted in growth retardation, and repeated blistering led to excessive induction of tissue repair, causing TGF-beta1-mediated contractile fibrosis generated by myofibroblasts and pseudosyndactyly in the extremities. Intradermal injection of WT fibroblasts resulted in neodeposition of collagen VII and functional restoration of the dermal-epidermal junction. Treated areas were also resistant to induced frictional stress. In contrast, untreated areas of the same mouse showed dermal-epidermal separation following induced stress. These data demonstrate that fibroblast-based treatment can be used to treat DEB in a mouse model and suggest that this approach may be effective in the development of clinical therapeutic regimens for patients with DEB.

Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia.

One hundred and ninety eight men seropositive for human immunodeficiency virus (HIV) antibody and 58 HIV antibody seroconverters were studied for an average of 19.3 (SEM 0.5) months to assess the relation between HIV antigenaemia and the risk of developing the acquired immune deficiency syndrome (AIDS) and AIDS related complex. Forty (20.2%) of the 198 HIV antibody seropositive men were antigen positive at entry and remained so during follow up. Eight (13.8%) of the 58 HIV antibody seroconverters and 20 (12.7%) of the remaining 158 HIV antibody seropositive men became antigen positive during follow up, resulting in an end point attack rate for HIV antigenaemia of 14.3%. AIDS related complex was diagnosed in 25 (15.8%) of the HIV antigen negative men and in 14 (20.7%) of the HIV antigen positive men. AIDS was diagnosed in 15 men, resulting in an end point attack rate for AIDS of 23.9% in the HIV antigen positive group and 1.3% in the antigen negative group. HIV antibody seropositive men without symptoms but with persistent HIV antigenaemia are at increased risk of developing AIDS and AIDS related complex.

T2-weighted balanced SSFP imaging (T2-TIDE) using variable flip angles.

A new technique for acquiring T2‐weighted, balanced steady‐state free precession (b‐SSFP) images is presented. Based on the recently proposed transition into driven equilibrium (TIDE) method, T2‐TIDE uses a special flip angle scheme to achieve T2‐weighted signal decay during the transient phase. In combination with half‐Fourier image acquisition, T2‐weighted images can be obtained using T2‐TIDE. Numerical simulations were performed to analyze the signal behavior of T2‐TIDE in comparison with TSE and b‐SSFP. The results indicate identical signal evolution of T2‐TIDE and TSE during the transient phase. T2‐TIDE was used in phantom experiments, and quantitative ROI analysis shows a linear relationship between TSE and T2‐TIDE SNR values. T2‐TIDE was also applied to abdominal and head imaging on healthy volunteers. The resulting images were analyzed quantitatively and compared with standard T2‐weighted and standard b‐SSFP methods. T2‐TIDE images clearly revealed T2 contrast and less blurring compared to T2‐HASTE images. In combination with a magnetization preparation technique, STIR‐weighted images were obtained. T2‐TIDE is a robust technique for acquiring T2‐weighted images while exploiting the advantages of b‐SSFP imaging, such as high signal‐to‐noise ratio (SNR) and short TRs. Magn Reson Med, 2006.

3D-imaging of the knee with an optimized 3D-FSE-sequence and a 15-channel knee-coil.

OBJECTIVES To evaluate the clinical usefulness of an optimized 3D-Fast-Spin-Echo-sequence (3D-SPACE) in combination with a 15-channel knee-coil for 3D-imaging of the knee at 3T. METHODS 15 volunteers and 50 consecutive patients were examined at 3 T with fat-saturated moderately T2-weighted 3D-SPACE (Voxel-size (VS): 0.6 mm×0.5 mm×0.5 mm/acquisition-time (AT) 10:44 min) using a 15-channel knee-coil. Flip angle optimization and radial k-space reordering were applied. Signal- and contrast-to-noise-ratios (SNR, CNR) were compared to non-optimized 3D-SPACE (8-channel knee-coil) and conventional 2D-FSE (VS: 0.4 mm×0.4 mm×3 mm/total AT: 12 min). Two radiologists independently rated depiction of internal knee structures and assessed detection and depiction of cartilage and meniscus abnormalities compared to conventional 2D-FSE-sequences. Sensitivity and specificity were calculated for a subgroup with arthroscopy as reference standard. Statistical analysis was performed with paired t-tests, confidence intervals and weighted-κ-coefficients. RESULTS SNR and CNR particularly of fluid/cartilage of optimized 3D-SPACE were significantly higher (p<0.05) than of the non-optimized 3D-sequence and conventional 2D-sequence. Blurring and image inhomogeneity were reduced in the optimized sequence. The thin slice-thickness was beneficial for depiction of problematical anatomical structures such as meniscal roots. 3D-SPACE showed significantly higher diagnostic confidence (p<0.05) for diagnosis of cartilage lesions of the femoral trochlea. Overall sensitivity and specificity of 3D-SPACE and 2D-FSE for cartilage lesions was 82.3%/80.2% and 79.4%/84.2% and 100%/86.4% and 92.3%/81.8% for meniscus lesions. CONCLUSIONS Optimized 3D-SPACE provides significantly higher signal and contrast compared to conventional 2D-FSE, particularly for fluid and cartilage, leading to improved diagnostic confidence, particularly in problematic areas, such as the femoral trochlea.

Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis

Objectives To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA). Methods 33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured. Results Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes. Discussion These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.

Intrinsic fat suppression in TIDE balanced steady-state free precession imaging.

A novel fat‐suppressed balanced steady‐state free precession (b‐SSFP) imaging method based on the transition into driven equilibrium (TIDE) sequence with variable flip angles is presented. The new method, called fat‐saturated (FS)‐TIDE, exploits the special behavior of TIDE signals from off‐resonance spins during the flip angle ramp. As shown by simulations and experimental data, the TIDE signal evolution for off‐resonant isochromats during the transition from turbo spin‐echo (TSE)‐like behavior to the true fast imaging with steady precession (TrueFISP) mode undergoes a zero crossing. The resulting signal notch for off‐resonant spins is then used for fat suppression. The efficiency of FS‐TIDE is demonstrated in phantoms and healthy volunteers on a 1.5T system. The resulting images are compared with standard TrueFISP data with and without fat suppression. It is demonstrated that FS‐TIDE provides a fast and stable means for homogenous fat suppression in abdominal imaging while maintaining balanced SSFP‐like image contrast and signal‐to‐noise ratio (SNR). The scan time of FS‐TIDE is not increased compared to normal TrueFISP imaging without fat suppression and identical k‐space trajectories. Because of the intrinsic fat suppression, no additional preparation is needed. Possible repetition times (TRs) are not firmly limited to special values and are nearly arbitrary. Magn Reson Med, 2006.

Cerebral correlates of heart rate variations during a spontaneous panic attack in the fMRI scanner.

We report the first published case study of a suddenly occurring panic attack in a patient with no prior history of panic disorder during combined functional magnetic resonance imaging (fMRI, 1.5 Tesla) and electrocardiogram (ECG) recording. The single case was a 46-year-old woman who developed a panic attack near the planned end of the fMRI acquisition session, which therefore had to be aborted. Correlational analysis of heart rate fluctuations and fMRI data revealed a significant negative association in the left middle temporal gyrus. Additionally, regions-of-interest (ROI) analyses indicated significant positive associations in the left amygdala, and trends towards significance in the right amygdala and left insula.