Stress analysis of carotid plaque based on in vivo MRI of acute symptomatic and asymptomatic patients

Stress analysis within carotid plaques based on in vivo MR imaging has shown to be useful for the identification of vulnerable atheroma. This study is to investigate whether magnetic resonance imaging (MRI) based-biomechanical stress analysis of carotid plaques can differentiate acute symptomatic and asymptomatic patients. 54 asymptomatic and 45 acute symptomatic patients underwent in vivo multi-contrast MRI of the carotid arteries. Plaque geometry used for finite element analysis was derived from in vivo MR images at the site of maximum and minimum plaque burden. In total 198 slices were used for the computational simulations. A pre shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (i.e. critical stress) was extracted for the selected slices and a comparison was performed between the two groups. Critical stress at the site of maximum plaque burden is significantly higher in acute symptomatic patients as compared to asymptomatic patients [median: 198.0kPa (inter quartile range (IQR) = (119.8 - 359.0) vs. 138.4kPa (83.8, 242.6), p=0.04]. No significant difference was found at the minimum plaque burden site between the two groups [196.7kPa (133.3- 282.7) vs. 182.4kPa (117.2 - 310. 6), p=0.82). Stress analysis at the site of maximal plaque burden can be effectively used for differentiating acute symptomatic carotid plaques from asymptomatic plaques. This maybe potentially used for development of biomechanical risk stratification criteria based on plaque burden in future studies.

MRI-based measurement of carotid mechanical properties in asymptomatic patients

Arterial mechanical property may be a potential variable for risk stratification. Large artery and central arterial compliance have been shown not only to correlate well with overall cardiovascular outcome in large epidemiological studies [1, 2] but also to correlate with coronary atherosclerotic burden as measured by conventional angiography [3]. Until recently, real-time B-mode ultrasound combined with simultaneous blood pressure measurements have been used to assess large artery compliance [4]. These techniques have an excellent temporal resolution but are unable to provide adequate spatial resolution to determine changes in vessel area as opposed to diameter and make the assumption that the vessel is perfectly round. Attempts to use MR imaging to measure large artery compliance have been published previously [5]. However, they have not utilised simultaneous blood pressure measurements during sequence acquisition. We report a technique using regular and simultaneous blood pressure measurement during 2 dimensional phase contrast magnetic resonance imaging 2DPC-MRI to determine local carotid compliance.

Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous cap: A comparison of symptomatic and asymptomatic individuals

Background and purpose: Inflammation is a risk factor the vulnerable atheromatous plaque. This can be detected in vivo on high-resolution magnetic resonance (MR) imaging using a contrast agent, Sinerem™, an ultra-small super-paramagnetic iron oxide (USPIO). The aim of this study was to explore whether there is a difference in the degree of MR defined inflammation using USPIO particles, between symptomatic and asymptomatic carotid plaques. We report further on its T1 effect of enhancing the fibrous cap, which may allow dual contrast resolution of carotid atheroma. Methods: Twenty patients with carotid stenosis (10 symptomatic and 10 asymptomatic) underwent multi-sequence MR imaging before and 36 h post-USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant was calculated following USPIO administration. Mean signal change across all quadrants were compared between the two groups. Results: Symptomatic patients had significantly more quadrants with a signal drop than asymptomatic individuals (75% vs. 32%, p < 0.01). Asymptomatic plaques had more quadrants with signal enhancement than symptomatic ones (68% vs. 25%, p < 0.05); their mean signal change was also higher (46% vs. 15%, p < 0.01) and this appeared to correlate with a thicker fibrous cap on histology. Conclusions: Symptomatic patients had more quadrants with signal drop suggesting larger inflammatory infiltrates. Asymptomatic individuals showed significantly more enhancement possibly suggesting greater stability as a result of thicker fibrous caps. However, some asymptomatic plaques also had focal areas of signal drop, suggesting an occult macrophage burden. If validated by larger studies, USPIO may be a useful dual contrast agent able to improve risk stratification of patients with carotid stenosis and inform selection for intervention.

Characterisation of carotid atheroma in symptomatic and asymptomatic patients using high resolution MRI

Background and purpose: To prospectively evaluate differences in carotid plaque characteristics in symptomatic and asymptomatic patients using high resolution MRI. Methods: 20 symptomatic and 20 asymptomatic patients, with at least 50% carotid stenosis as determined by Doppler ultrasound, underwent preoperative in vivo multispectral MRI of the carotid arteries. Studies were analysed both qualitatively and quantitatively in a randomised manner by two experienced readers in consensus, blinded to clinical status, and plaques were classified according to the modified American Heart Association (AHA) criteria. Results: After exclusion of poor quality images, 109 MRI sections in 18 symptomatic and 19 asymptomatic patients were available for analysis. There were no significant differences in mean luminal stenosis severity (72.9% vs 67.6%; p = 0.09) or plaque burden (median plaque areas 50 mm2 vs 50 mm 2; p = 0.858) between the symptomatic and asymptomatic groups. However, symptomatic lesions had a higher incidence of ruptured fibrous caps (36.5% vs 8.7%; p = 0.004), haemorrhage or thrombus (46.5% vs 14.0%; p<0.001), large necrotic lipid cores (63.8% vs 28.0%; p = 0.002) and complicated type VI AHA lesions (61.5% vs 28.1%; p = 0.001) compared with asymptomatic lesions. The MRI findings of plaque haemorrhage or thrombus had an odds ratio of 5.25 (95% CI 2.08 to 13.24) while thin or ruptured fibrous cap (as opposed to a thick fibrous cap) had an odds ratio of 7.94 (95% CI 2.93 to 21.51) for prediction of symptomatic clinical status. Conclusions: There are significant differences in plaque characteristics between symptomatic and asymptomatic carotid atheroma and these can be detected in vivo by high resolution MRI.

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: An ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study

Introduction: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). Methods: 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. Results: The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p < 0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p < 0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p = 0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p < 0.001). Conclusions: These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.

In vivo positive contrast IRON sequence and quantitative T2* measurement confirms inflammatory burden in a patient with asymptomatic carotid atheroma after USPIO-enhanced MR Imaging

The authors report an in vivo human examination of carotid atheroma by using the inversion-recovery ON resonance (IRON) sequence, which is able to produce positive contrast after the infusion of an ultrasmall super paramagnetic iron oxide (USPIO) contrast medium. This technique provides a method of potentially identifying inflammatory burden within carotid atheroma. This may be particularly useful in patients who currently do not meet criteria for intervention (ie, moderate symptomatic stenosis or <70% asymptomatic stenosis) to further risk-stratify this important patient cohort. A 63-year-old man was imaged at 1.5 T before and 36 hours after USPIO infusion by using the IRON sequence. Regions of interest showing profound signal loss at T2*-weighted imaging corresponded well with regions of positive contrast at IRON imaging after the administration of USPIO. These regions also showed a profound decrease in T2* measurements after USPIO infusion, whereas surrounding tissue did not. It has been shown that such strong signal loss on T2*-weighted images after USPIO infusion is indicative of USPIO uptake.

Structural analysis and magnetic resonance imaging predict plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

Background: More than half of all cerebral ischemic events are the result of rupture of extracranial plaques. The clinical determination of carotid plaque vulnerability is currently based solely on luminal stenosis; however, it has been increasingly suggested that plaque morphology and biomechanical stress should also be considered. We used finite element analysis based on in vivo magnetic resonance imaging (MRI) to simulate the stress distributions within plaques of asymptomatic and symptomatic individuals. Methods: Thirty nonconsecutive subjects (15 symptomatic and 15 asymptomatic) underwent high-resolution multisequence in vivo MRI of the carotid bifurcation. Stress analysis was performed based on the geometry derived from in vivo MRI of the carotid artery at the point of maximal stenosis. The finite element analysis model considered plaque components to be hyperelastic. The peak stresses within the plaques of symptomatic and asymptomatic individuals were compared. Results: High stress concentrations were found at the shoulder regions of symptomatic plaques, and the maximal stresses predicted in this group were significantly higher than those in the asymptomatic group (508.2 ± 193.1 vs 269.6 ± 107.9 kPa; P = .004). Conclusions: Maximal predicted plaque stresses in symptomatic patients were higher than those predicted in asymptomatic patients by finite element analysis, suggesting the possibility that plaques with higher stresses may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, biomechanical stress analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma. It may help in the identification of patients with asymptomatic carotid atheroma at greatest risk of developing symptoms or mild-to-moderate symptomatic stenoses, which currently fall outside current clinical guidelines for intervention.

Non-invasive MR imaging of inflammation in a patient with both asymptomatic carotid atheroma and an abdominal aortic aneurysm: A case report

Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. USPIO-enhanced MRI imaging is a promising non-i nvasive method to identify high-risk atheromatous plaque inflammation in vivo in humans, in which areas of focal signal loss on MR images have been shown to correspond to the location of activated macrophages, typically at the shoulder regions of the plaque. This is the first report in humans describing simultaneous USPIO uptake within atheroma in two different arterial territories and again emphasises that atherosclerosis is a truly systemic disease. With further work, USPIO-enhanced MR imaging may be useful in identifying inflamed vulnerable atheromatous plaques in vivo, so refining patient selection for intervention and allowing appropriate early aggressive pharmacotherapy to prevent plaque rupture.

The stock structure of grey mackerel Scomberomorus semifasciatus in Australia as inferred from its parasite fauna

The scombrid Scomberomorus semifasciatus is an important component of inshore fisheries in tropical Australia. Data on the parasite fauna of 593 fish from areas off northern and eastern Australia were examined for evidence of discrete fish populations. The parasites used were juveniles of Pterobothrium pearsoni, Callitetrarhynchus gracilis, Anisakis simplex (sensu latu) and Terranova sp. Tukey Kramer pairwise comparisons gave significant differences in the abundances of two or more parasites between fish from the east coast, the eastern Gulf of Carpentaria and the remainder of northern Australia. Multivariate analysis gave further evidence of differences and the results suggest that at least 4 populations or stocks of grey mackerel occur along the northern and eastern coastline of Australia.

The role of AIP and CDKN1B/p27Kip1 in endocrine neoplasia

Identification of genes predisposing to tumor syndromes has raised general awareness of tumorigenesis. Genetic testing of tumor susceptibility genes aids the recognition of individuals at increased risk of tumors. Identification of novel predisposing genes enables further studies concerning the classification of potential associated tumors and the definition of target patient group. Pituitary adenomas are common, benign neoplasms accounting for approximately 15% of all intracranial tumors. Accurate incidence estimation is challenging since a great portion of these adenomas are small and asymptomatic. Clinically relevant adenomas, that cause symptoms due to the expansion of the cell mass or the over-secretion of normally produced hormones, occur in approximately one of 1 000 individuals. Although the majority of pituitary adenomas are sporadic, a minority occur as components of familial syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1) and Carney complex (CNC). MEN1 syndrome is caused by germ-line mutations in the MEN1 gene, whereas most of the CNC patients carry the mutated protein kinase A (PKA) regulatory subunit-1-α (PRKAR1A) gene. Recently, other conditions predisposing to endocrine tumors have been identified: Pituitary Adenoma Predisposition (PAP) and MEN type 4 (MEN4). PAP was originally identified in a genetically homogeneous Finnish population. In a population based cohort from Northern Finland, aryl hydrocarbon receptor-interacting protein (AIP) gene mutations were found in 16% of all patients diagnosed with growth hormone (GH) producing pituitary adenoma, and in 40% of the subset of patients who were diagnosed under the age of 35 years. Since AIP mutations were originally described in a defined, homogeneous population from Northern Finland, it was relevant to study whether mutations also occur in more heterogeneous populations. In patient cohorts with different ethnic origins and variable clinical phenotypes, germ-line AIP mutations were detectable at low frequencies (range 0.8-7.4%). AIP mutation-positive patients were often diagnosed with a GH-producing adenoma at a young age, and usually had no family history of endocrine tumors. The low frequency of AIP mutations in randomly selected patients, and the lack of any family history of pituitary adenomas create a challenge for the identification of PAP patients. Our preliminary study suggests that AIP immunohistochemistry may serve as a pre-screening tool to distinguish between the AIP mutation-negative and the mutation-positive tumors. Tumors of various endocrine glands are components of MEN1 and CNC syndromes. Somatic MEN1 and PRKAR1A mutations in sporadic pituitary adenomas are rare, but occur in some of the other tumors related to these syndromes. The role of AIP mutations in endocrine neoplasia was studied and our results indicated that somatic AIP mutations are rare or non-existent in sporadic tumors of endocrine glands (0 of 111). Furthermore, germ-line AIP mutations in prolactin producing adenomas (2 of 9) confirmed the role of this pituitary tumor type in the PAP phenotype. Thyroid disorders are common in the general population, and the majority of them are sporadic. Interestingly, it has been suggested that thyroid disorders might be more common in PAP families. For this reason we studied germ-line AIP mutations in 93 index cases from familial non-medullary thyroid cancer (NMTC) families. The underlying gene or genes for familial NMTC have not been identified yet. None of the patients had any potentially pathogenic AIP mutation. This suggests that AIP is unlikely to play a role in familial NMTCs. A novel multiple endocrine syndrome was originally described in rats with phenotypic features of human MEN type 1 and 2. Germ-line mutations of cyclin-dependent kinase inhibitor 1B (CDKN1B also known as p27Kip1) gene were reported later in these rats and a germ-line mutation was also identified in one human family with MEN1-like phenotype (later named MEN4). To confirm the importance of this gene’s mutations in humans, we performed a mutation screening in MEN-like patients and in patients with pituitary adenoma. Our results indicate that CDKN1B/p27Kip1 mutations appear in a small portion of MEN1-like patients (one of 36), and that such mutations are rare or non-existent in both familial (0 of 19) and sporadic pituitary adenoma patients (0 of 50). In conclusion, this work strengthens the tumor susceptibility role of AIP and CDKN1B/p27Kip1 in endocrine neoplasia. Clarifying the PAP phenotype facilitates the identification of potential AIP mutation carriers. Genetic counseling can be offered to the relatives and follow-up of the mutation carriers can be organized, hence an earlier diagnosis is feasible.

The decline of northern malaria and population dynamics of Plamodium vivax

Europe was declared malaria free in 1975. The disappearance of malaria has traditionally been attributed to numerous deliberate actions like vector control, the screening of houses, more efficient medication etc. Malaria, however, disappeared from many countries like Finland before any counter measures had even started. The aim of this thesis is to study the population ecology of P. vivax and its interaction with the human host and the vector. By finding the factors that attributed to the extinction of vivax malaria it might be possible to improve the modern strategy against P. vivax. The parasite was studied with data from Finland, which provides the longest time series (1749-2008) of malaria statistics in the world. The malaria vectors, Anopheles messeae and A. beklemishevi are still common species in the country. The eradication of vivax malaria is difficult because the parasite has a dormant stage that can cause a relapse long after a primary infection. It was now shown that P. vivax is able to detect the presence of a potential vector. A dormant stage is triggered even from a bite of an uninfected Anopheles mosquito. This optimizes the chances for the Plasmodium to reach a mosquito vector for sexual reproduction. The longevity of the dormant stage could be shown to be at least nine years. The parasite spends several years in its human host and the behaviour of the human carrier had a profound impact on the decline of the disease in Finland. Malaria spring epidemics could be explained by a previous warm summer. Neither annual nor summer mean temperature had any impact on the long term malaria trend. Malaria disappeared slowly from Finland without mosquito control. The sociological change from extended families to nuclear families led to decreased household size. The decreased household size correlated strongly with the decline of malaria. That led to an increased isolation of the subpopulations of P. vivax. Their habitat consisted of the bedrooms in which human carriers slept together with the overwintering vectors. The isolation of the parasite ultimately led to the extinction of vivax malaria. Metapopulation models adapted to local conditions should therefore be implemented as a tool for settlement planning and socio-economic development and become an integrated part of the fight against malaria.

Some investigations on secondary breakdown in p-n junctions considering the effect of thermally generated carriers

The V-I characteristic of a p-n junction under breakdown is calculated taking the thermally generated carriers into account. The current density distributions computed under different conditions have been given. The light emission and other characteristics reported by Chiang and Lauritzen and others have been explained.

Surveillance in hereditary nonpolyposis colorectal cancer syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited cancer predisposition syn-drome characterized by early onset colorectal cancer (CRC) and several other extra-colonic cancers, most commonly endometrial cancer (EC) and gastric cancer. Our aim was to evaluate the efficiency and results of the ongoing CRC and EC surveillance programs and to investigate the grounds for future gastric cancer screening by comparing the gastric biopsies of mutation positive and negative siblings in search for premalignant lesions. We also compared a new surveillance method, computerized tomographic colonoscopy (CTC) with optic colonoscopy. The patient material consisted of 579 family members from 111 Finnish HNPCC families al-most all harboring a known mismatch repair gene mutation. The efficacy of CRC and EC surveillance programs on HNPCC patients was evaluated by comparing the stage and survival of cancer cases detected with surveillance versus without. The performance of a new technique, CTC, was explored using a same-day colonoscopy as a reference standard. The use of intrauterine aspiration biopsies for EC surveillance was intro-duced for the first time in a HNPCC setting. Upper GI endoscopies were performed and biop-sies taken from mutation carriers and their mutation-negative siblings. The present surveillance program for CRC proved to be efficient. The CRC cases detected by surveillance were at a significantly more favorable stage than those in the non-surveilled group. This advantage was reflected in a significantly higher CRC-specific survival in the sur-veilled group. The performance of a new technique, CTC was found insufficient for polyp detection in this population in which every polyp, no matter the size, should be detected and removed. Colono-scopy was confirmed as a better surveillance modality than CTC. We could not observe any of the assumed differences in the gastric mucosa from mutation carriers and their mutation-negative siblings and no cases of gastric cancer were detected. The results gave no support for gastric surveillance. The EC surveillance program (transvaginal ultrasound and intra-uterine biopsy every 2-3 years) seemed to be efficient. It yielded several asymptomatic cancer cases and premalignant lesions. The stage distribution of the endometrial cancers in the group under surveillance tended to be more favorable than that of the mutation-positive, symptomatic EC patients who had no surveillance. None of the surveilled EC patients died of EC compared to six in the non-surveilled patients during the follow up. The improvement was, however, not statistically sig-nificant, thus far. Another observation was the good performance of endometrial aspiration biopsies used in this setting for the first time.

Cutaneous porphyrias : Clinical and histopathological study

The prevalence of variegate porphyria (VP) (2.1:100 000, in 2006 n=108) was higher in Finland than elsewhere in European countries due to a founder effect (R152C). The incidence of VP was estimated at 0.2:1 000 000 based on the number of new symptomatic patients yearly. The prevalence of porphyria cutanea tarda (PCT) was 1.2:100 000 (in 2006 n=63), which is only one fourth of the numbers reported from other European countries. The estimated incidence of PCT was 0.5:1 000 000. Based on measurements of the uroporphyrinogen decarboxylase activity in erythrocytes, the proportion of familial PCT was 49% of the cases. The prevalence of erythropoietic protoporphyria (EPP) was at 0.8:100 000 (in 2006 n=39) including asymptomatic carriers of a mutation in the ferrochelatase (FECH) gene. The incidence of EPP was estimated at 0.1:1 000 000. After 1980 the penetrance was 37% among patients with VP. Of the mutation carriers (n=57) 30% manifested with skin symptoms. Frequency of skin symptom as only clinical sign was stable before or after 1980 (22% vs. 21%), but acute attacks became infrequent (29% vs. 7%). Of the symptomatic patients 30% had both acute attacks and skin symptoms and 80% had skin symptoms. Fragility (95%) and blistering (46%) of the skin in the backs of the hands were the most common skin symptoms. Transient correction of porphyrin metabolism using eight haem arginate infusions within five weeks had no effect on the skin symptoms in three of four patients with VP. In one case skin symptoms disappeared transiently. One patient with homozygous VP had severe photosensitivity since birth. Sensory polyneuropathy, glaucoma and renal failure developed during the 25-year follow-up without the presence of acute attacks. The I12T mutation was detected in both of his alleles in the protoporphyrinogen oxidase gene. Lack of skin symptoms and infrequency of acute attacks (1/9) in the patients with I12T mutation at the heterozygous stage indicate a mild phenotype (the penetrance 11%). Four mutations (751delGAGAA, 1122delT, C286T, C343T) in the FECH gene were characterised in four of 15 families with EPP. Burning pain (96%) and swelling (92%) of the sun-exposed skin were the major skin symptoms. Hepatopathy appeared in one of 25 symptomatic patients (4%). Clinical manifestations and associated factors of PCT were similar in the sporadic and familial types of PCT. The majority of the patients with PCT had one to three precipitating factors: alcohol intake (78%), mutations in hemochromatosis associated gene (50%), use of oestrogen (25% of women) and hepatitis B or C infections (25 %). Fatty liver disease (67%) and siderosis (67%) were commonly found in their liver biopsies. The major histopathological change of the sun-exposed skin in the patients with VP (n=20), EPP (n=8) and PCT (n=5) was thickening of the vessel walls of the upper dermis suggesting that the vessel wall is the primary site of the phototoxic reaction in each type of porphyria. The fine structure of the vessel walls was similar in VP, EPP and PCT consisting of the multilayered basement membrane and excess of finely granular substance between the layers which were surrounded by the band of homogenous material. EPP was characterised by amorphous perivascular deposits extending also to the extravascular space. In direct immunofluorescence study homogenous IgG deposits in the vessel walls of the upper dermis of the sun-exposed skin were demonstrated in each type of porphyria. In EPP the excess material around vessel walls consisted of other proteins such as serum amyloid protein, and kappa and lambda light chains in addition to the basement membrane constituents such as collagen IV and laminin. These results suggest that the alterations of the vessel walls are a consequence of the repeated damage and the repairing process in the vessel wall. The microscopic alterations could be demonstrated even in the normal looking but sun-exposed skin of the patients with EPP during the symptom-free phase suggesting that vascular change can be chronic. The stability of vascular changes in the patients with PCT after treatment indicates that circulating porphyrins are not important for the maintenance of the changes.