Trial of canakinumab, an IL-1ß receptor antagonist, in patients with inclusion body myositis.

Objective: To assess whether canakinumab, a monoclonal antibody against IL-1ß approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM). Methods: Because in sIBM IL-1ß colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1ß with canakinumab may arrest disease progression. On this basis, 5 ambulatory patients with sIBM participated in an institutional review board--approved open-labeled study with 150 mg canakinumab [4 bimonthly, then monthly subcutaneous injections] for a mean period of 15.8 months. Patients were assessed bimonthly with a manual dynamometer in 12 proximal and distal muscles and with grip force (GF) in both hands. Total muscle strength (TMS) was expressed in kilograms. Efficacy was defined as >15% increased strength after 12 months. Results: Patient 1 stopped at month 5 because of 23% loss in TMS and 32.35% in GF; patient 2 showed 37.1% increase in TMS and 13% in GF by month 9; patient 3 exhibited 26.7% reduction in TMS and 10% in GF at month 33; patient 4 showed 6.5% reduction in TMS and 1.6% in GF after 15 months, denoting relative stability; and patient 5 showed 30.4% loss in TMS and 20.8% in GF after 18 months. In patients 2 and 4, in whom 3-year longitudinal data were available, no effect on disease progression was noted. Conclusions: In this long-term, open-label study, canakinumab showed small, but not clinically appreciable, stabilizing benefits in 2 of 5 patients with sIBM over 1 year, was ineffective in 2 others, and might have worsened one. No patient improved. Classification of evidence: This study provides Class IV evidence that canakinumab was ineffective for patients with sIBM.

Differences in cardiac structure assessed by echocardiography between renal transplant recipients and chronic kidney disease patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in predialysis chronic kidney disease (CKD) and dialysis patients as well as in renal transplant recipients (RTRs). Left ventricular hypertrophy (LVH) starts early during the course of CKD and is a strong predictor of CVD in this population. Regression of LVH after a successful renal transplantation remains a debatable issue among investigators, whereas there is little data comparing echocardiographic measurements between patients with predialysis CKD and RTRs. AIM: The aim of this study was to compare echocardiographic measurements of LV structure and function between predialysis CKD patients and RTRs of similar renal function level. PATIENTS AND METHODS: We conducted a case control study with individual (1:2) matching from the Renal Transplant and the predialysis CKD Outpatient Clinic. For each of the 36 RTRs, two matched for gender, age and estimated glomerular filtration rate (eGFR) predialysis CKD outpatients (72 patients) were included. All patients underwent transthoracic echocardiography and LV mass, LV mass index [LVM and LVMI = LVM/BSA g/m(2)] and indices of systolic function were measured. In a subgroup of 12 RTRs we retrospectively assessed and compared the LVMI measurements at three different time points, during predialysis, dialysis and post transplant period. RESULTS: The prevalence of LVH was 33% in RTRs and 52% in CKD patients (ns). RTRs had significantly lower LVM and LVMI levels compared with predialysis CKD patients (P = .006 and P = .008) while the other echocardiographic indices did not differ. In the subgroup of 12 RTRs, post-transplant LVMI levels (105 ± 25 g/m(2)) were significantly lower in comparison with predialysis (147 ± 57 g/m(2)) and dialysis LVMI levels (169 ± 72 g/m(2)) (P = .01, P = .01, respectively). CONCLUSION: RTRs had significantly lower LVMI compared with predialysis CKD patients of similar age, renal function, hemoglobin and blood pressure level.

Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study.

OBJECTIVES: Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN). DESIGN, SETTING AND PARTICIPANTS: We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain. RESULTS: 15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6-12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8-11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p<0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease. CONCLUSION: This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients.

The effect of anakinra, an IL1 receptor antagonist, in patients with sporadic inclusion body myositis (sIBM): a small pilot study.

In sIBM, an inflammatory process mediated by cytotoxic T cells and cytokines in conjunction with a degenerative process, deposits of beta amyloid and misfolded proteins appear to be the main culprits in disease pathogenesis. IL-1ß may play a key role because it is upregulated in sIBM myofibers, co-localizes with Amyloid Precursor Protein (APP) and promotes the production of APP and amyloid deposits. We performed a small, pilot study to examine whether anakinra, an IL1 receptor antagonist could benefit sIBM patients. Four patients with biopsy-proven sIBM received anakinra for a mean period of 7.7 months. No improvement in muscle strength or stabilization was noted in any of the patients based on grip strength and MRC measurements. The treatment failure may be due to insufficiency of anakinra to suppress the intramuscular IL1, the short study period, or the irrelevance of IL1 in the disease process.

Incidence and prevalence of major central nervous system involvement in systemic lupus erythematosus: a 3-year prospective study of 370 patients.

BACKGROUND: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. METHODS: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. RESULTS: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P≤0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P<0.001). CONCLUSIONS: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes.

3D reconstruction of coronary arteries using frequency domain optical coherence tomography images and biplane angiography.

The aim of this study is to describe a new method for three-dimensional (3D) reconstruction of coronary arteries using Frequency Domain Optical Coherence Tomography (FD-OCT) images. The rationale is to fuse the information about the curvature of the artery, derived from biplane angiographies, with the information regarding the lumen wall, which is produced from the FD-OCT examination. The method is based on a three step approach. In the first step the lumen borders in FD-OCT images are detected. In the second step a 3D curve is produced using the center line of the vessel from the two biplane projections. Finally in the third step the detected lumen borders are placed perpendicularly onto the path based on the centroid of each lumen border. The result is a 3D reconstructed artery produced by all the lumen borders of the FD-OCT pullback representing the 3D arterial geometry of the vessel.

Endovascular abdominal aortic aneurysm repair: methods of radiological risk reduction.

AIM: The management of abdominal aortic aneurysm with endovascular repair (EVAR) requires extended exposure to ionizing radiation, before, during and after the intervention. The aim of this study was to quantify the radiological risks to patients and operating team, and to develop strategies to assess and reduce them. METHODS: EVAR was carried out in 97 patients using either a low-power mobile or a high-power stationary fluoroscopic unit. Empirically determined relationships between the indicated dose area product (DAP) and peak skin dose, obtained by direct in vivo dosimetry in a subgroup of patients, were used to predict the peak skin dose. Individual worker monitoring was used to assess personnel radiological burden. RESULTS: The probability for radiation induced biological effects due to the repair itself and the preoperative and life-long surveillance, as carried out, was about 2.4 10-3. The peak skin dose of repairs was linearly correlated with the DAP and did not exceed 1.2 Gy. The collective effective dose of the staff that carried out repairs using the mobile unit was 5.5 and 8 µSv per repair using an angiographic and a surgical table, respectively. The use of the high-power fluoroscopic unit resulted in a many fold higher radiation burden to both patient and personnel. CONCLUSION: The optimum strategy, including equipment-related factors, procedure-conduct factors and follow-up procedures, has to be studied, justified and optimized in each medical facility.

Multiscale-patient-specific artery and atherogenesis models.

In this work, we present a platform for the development of multiscale patient-specific artery and atherogenesis models. The platform, called ARTool, integrates technologies of 3-D image reconstruction from various image modalities, blood flow and biological models of mass transfer, plaque characterization, and plaque growth. Patient images are acquired for the development of the 3-D model of the patient specific arteries. Then, blood flow is modeled within the arterial models for the calculation of the wall shear stress distribution (WSS). WSS is combined with other patient-specific parameters for the development of the plaque progression models. Real-time simulation can be performed for same cases in grid environment. The platform is evaluated using both animal and human data.

Atherosclerotic plaque characterization in Optical Coherence Tomography images.

Optical Coherence Tomography (OCT) is a fiber--optic imaging modality which produces high resolution tomographic images of the coronary lumen and outer vessel wall. While OCT images present morphological information in highly resolved detail, the characterization of the various plaque components relies on trained readers. The aim of this study is to extract a set of features in grayscale OCT images and to use them in order to classify the atherosclerotic plaque. Intensity and texture based features we used in order to classify the plaque in four plaque types: Calcium (C), Lipid Pool (LP), Fibrous Tissue (FT) and Mixed Plaque (MP). 50 OCT annotated images from 3 patients were used to train and test the proposed plaque characterization method. Using a Random Forests classifier overall classification accuracy 80.41% is reported.

Simultaneous endovascular stent-graft repair of descending thoracic and abdominal aortic pathologies. Report of four cases.

Four patients suffering from concomitant descending thoracic pathology and abdominal aortic aneurysms were treated with endovascular stent-grafts simultaneously. Graft deployment was successful and uneventful in all patients. Paraplegia was not observed. One patient developed an abdominal type Ib endoleak at 12 months which was repaired endovascularly. One patient died from multiorgan failure 3 days after the deployment of the grafts. After 18, 36 and 42 months follow up all the other patients are well without any graft related complication. Simultaneous endovascular repair for coexisting descending thoracic and abdominal aortic pathologies might be an acceptable alternative to open surgery or hybrid operations, at least for the high risk patients.

Balloon angioplasty optimization: should we measure balloon volume as well as pressure?

PURPOSE: To investigate the influence that measurement of balloon volume as a controlled variable in addition to balloon pressure has on the outcome of balloon angioplasty in an experimental model. METHODS: One hundred and three segments of explanted normal porcine carotid arteries were obtained. Five were used as controls, and the remaining 98 were subjected to balloon angioplasty with simultaneous measurement of balloon volume and pressure. These arteries were randomized into two groups. In one group the endpoint of the angioplasty was determined by balloon pressure (pressure-limited group, PLG) and in the other group by balloon volume (volume-limited group, VLG). Pressure/volume curves for each procedure were constructed by continuous measurement of both parameters by a purpose-designed computer-controlled inflation device. The diameter of each arterial segment was measured by intravascular ultrasound (IVUS) and the ratio of the inflated balloon to arterial diameter calculated. Arterial appearances after angioplasty were recorded using IVUS. RESULTS: The balloon volumes measured at the endpoint of angioplasty were significantly smaller in the PLG compared with the VLG (p < 0.001). Three types of pressure/volume curves were identified: A, B, and C. In the type A curves, IVUS identified fissures in 28% (17/60) and the examination was normal in 72% (43/60). In the type B curves, IVUS identified fissures in 44% (4/9), dissections in 22% (2/9), and the examination was normal in 33% (3/9). In the type C curves, IVUS identified fissures in 44% (4/9) and dissection in 56% (5/9) with no normal examinations. In undamaged arterial segments a very high correlation was achieved between balloon volume and the balloon/artery ratio (Pearson correlation = -0.979, R(2) = 0.957, p < 0.0001, n = 27). CONCLUSION: The measurement of pressure and volume during angioplasty enabled the construction of pressure/volume curves that showed deviations from the curves obtained in air. The balloon volume results, and significant deviation of the curve shape from the control curve shape, predicted vessel damage, which was confirmed by the IVUS appearance of the vessel after angioplasty. When pressure was used as the endpoint of balloon inflation the balloons were significantly underdilated compared with the manufacturer's nominal sizes. These data indicate that monitoring of pressure and volume during angioplasty may provide an alternative method of predicting vessel damage.

Phase resetting in one-dimensional model of the sinoatrial node.

In this paper, we use a one-dimensional model of the rabbit sinoatrial node (SAN), and we investigate the response of the model to hyperpolarizing and depolarizing stimulus. Depending on the stimulus timing, either a delay or an advance in the occurrence of next action potential is produced. This resetting behavior of the model is quantified in terms of phase transition curves (PTCs) for short electrical current pulses of varying amplitude which span the whole period. The main focus of this paper is to compare the dynamic properties of the spatially extended system and the single cell model. The detailed analysis of the results provides new insights in the understanding of the transition from the theoretical single cell models to the spatially extended systems.

Phase response characteristics of sinoatrial node cells.

In this work, the dynamic response of the sinoatrial node (SAN), the natural pacemaker of the heart, to short external stimuli is investigated using the Zhang et al. model. The model equations are solved twice for the central cell and for the peripheral cell. A short current pulse is applied to reset the spontaneous rhythmic activity of the single sinoatrial node cell. Depending on the stimulus timing either a delay or an advance in the occurrence of next action potential is produced. This resetting behavior is quantified in terms of phase transition curves (PTCs) for short electrical current pulses of varying amplitude which span the whole period. For low stimulus amplitudes the transition from advance to delay is smooth, while at higher amplitudes abrupt changes and discontinuities are observed in PTCs. Such discontinuities reveal critical stimuli, the application of which can result in annihilation of activity in central SAN cells. The detailed analysis of the ionic mechanisms involved in its resetting behavior of sinoatrial node cell models provides new insight into the dynamics and physiology of excitation of the sinoatrial node of the heart.

Anharmonic analysis of arterial blood pressure and flow pulses.

Fourier analysis is usually employed for the computation of blood flow in arteries. Although the orthogonality of Fourier eigenfunctions guarantees the accurate mathematical modeling of the blood pressure and flow waveforms, the physics behind this objective function is frequently missing. We propose a new method to account for the blood pressure and flow, single-cycle (systole-diastole) waveforms. It is based on the one dimensional hydrodynamic mass and momentum conservation equations for viscous flow. The similarity of the linear problem, under discussion, with related transmission line theory in electromagnetic wave propagation, permits expansion in anharmonic, non-separable eigenfunctions. In some cases one term in the expansion is adequate to fit the main peak of the observed waveforms. Analytical formulas are derived for the dependence of the pressure and flow main peaks on whole blood viscosity and distance from the heart, which interpret observations related to hypertension.

Patient and personnel dosimetry in endovascular radiotherapy with 90Sr/90Y sources.

Endovascular brachytherapy (EVBT) is an established treatment to reduce the probability of restenosis after a percutaneous coronary intervention. The purpose of this study was to assess (1) the manufacturer's stated dosimetric data for (90)Sr/(90)Y source trains to be used in EVBT and (2) the procedure-related radiation burden. The radiation fields in water around six (90)Sr/(90)Y source trains were studied using phantoms made of 'solid water' and MD55-2 radiochromic films. The water equivalence of the phantom material was tested by applying quantitative computed tomography. Thermoluminescence dosemeters were used to assess personal radiation burden and crosscheck the dose distribution along the source trains. Technical failure was observed in one source train and this train was excluded from analysis. The measured dose rate in water at 2 mm radial distance was on average 8% higher than the manufacture's stated value (range of measured to stated values 1.05--1.15). The dose rate decreased exponentially with radial distance between 2 and 6 mm. The dose rate in contact with the source viewing window of the delivery devices ranged between 0.5 and 7.5 mGy h(-1). Low-energy photons were the main contributors to personal dose.

In vivo validation of a novel semi-automated method for border detection in intravascular ultrasound images.

The aim of this work was to evaluate a new semi-automated intravascular ultrasound (IVUS) border detection method. The method was used to identify the lumen and the external elastic membrane or the borders of stents in 80 IVUS images, randomly selected from 10 consecutive human coronary arteries. These semi-automated results were compared with observations of two experts. Several indices in each case were obtained in order fully to evaluate the method. The time required for identification of the borders was also recorded. The interobserver variability of the method ranged from 1.21% to 5.61%, the correlation coefficient from 0.98 to 0.99, the slope was close to unity (0.94-1.03), the y intercept close to zero and the Williams index value was close to unity (range 0.67-0.91). The time (mean+/-SD) required for the method to identify the borders of the different vessel layers for the whole IVUS sequence was 5.2+/-0.2 min. The results demonstrate that the method is reliable and capable of identifying rapidly and accurately the different vessel layers depicted in IVUS images.

Treatment of acute lower limb ischemia following the use of the Duett sealing device: report of three cases and review of the literature.

Three cases of local thrombolysis in the treatment of acute lower limb ischemia complicating the utilization of the Duett sealing device are presented. Routine usage of several vascular closure devices after cardiac catheterization and percutaneous coronary intervention (PCI) has been adopted in our institution during the last 3 years (September 1999 to April 2003). The Duett closure device has been used in 420 patients (post-coronary angiography, 359; post-PCI, 61). Three patients (0.7%) demonstrated acute leg ischemia used by inadvertent intravascular administration of the sealing material related to this device. All three were treated successfully by catheter-directed local thromolysis (tissue plasminogen activator 5 mg bolus followed initially by 1 mg/hr and consequently by 0.5-1.0 mg/hr depending upon the development of significant hematoma and lasting for 24 hr). In conclusion, interventional treatment using local thrombolysis should be the first-line treatment in acute lower limb ischemia complicating the utilization of the Duett sealing device.