A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development.

Characterization of scatter in cone-beam CT breast imaging: comparison of experimental measurements and Monte Carlo simulation.

It is commonly understood that scattered radiation in x-ray computed tomography (CT) degrades the reconstructed image. As a precursor to developing scatter compensation methods, it is important to characterize this scatter using both empirical measurements and Monte Carlo simulations. Previous studies characterizing scatter using both experimental measurements and Monte Carlo simulations have been reported in diagnostic radiology and conventional mammography. The emerging technology of cone-beam CT breast imaging (CTBI) differs significantly from conventional mammography in the breast shape and imaging geometry, aspects that are important factors impacting the measured scatter. This study used a bench-top cone-beam CTBI system with an indirect flat-panel detector. A cylindrical phantom with equivalent composition of 50% fibroglandular and 50% adipose tissues was used, and scatter distributions were measured by beam stop and aperture methods. The GEANT4-based simulation package GATE was used to model x-ray photon interactions in the phantom and detector. Scatter to primary ratio (SPR) measurements using both the beam stop and aperture methods were consistent within 5% after subtraction of nonbreast scatter contributions and agree with the low energy electromagnetic model simulation in GATE. The validated simulation model was used to characterize the SPR in different CTBI conditions. In addition, a realistic, digital breast phantom was simulated to determine the characteristics of various scatter components that cannot be separated in measurements. The simulation showed that the scatter distribution from multiple Compton and Rayleigh scatterings, as well as from the single Compton scattering, has predominantly low-frequency characteristics. The single Rayleigh scatter was observed to be the primary contribution to the spatially variant scatter component.

Evaluation of a variable dose acquisition technique for microcalcification and mass detection in digital breast tomosynthesis.

In this article the authors evaluate a recently proposed variable dose (VD)-digital breast tomosynthesis (DBT) acquisition technique in terms of the detection accuracy for breast masses and microcalcification (MC) clusters. With this technique, approximately half of the total dose is used for one center projection and the remaining dose is split among the other tomosynthesis projection views. This acquisition method would yield both a projection view and a reconstruction view. One of the aims of this study was to evaluate whether the center projection alone of the VD acquisition can provide equal or superior MC detection in comparison to the 3D images from uniform dose (UD)-DBT. Another aim was to compare the mass-detection capabilities of 3D reconstructions from VD-DBT and UD-DBT. In a localization receiver operating characteristic (LROC) observer study of MC detection, the authors compared the center projection of a VD acquisitioh scheme (at 2 mGy dose) with detector pixel size of 100 microm with the UD-DBT reconstruction (at 4 mGy dose) obtained with a voxel size of 100 microm. MCs with sizes of 150 and 180 microm were used in the study, with each cluster consisting of seven MCs distributed randomly within a small volume. Reconstructed images in UD-DBT were obtained from a projection set that had a total of 4 mGy dose. The current study shows that for MC detection, using the center projection alone of VD acquisition scheme performs worse with area under the LROC curve (AL) of 0.76 than when using the 3D reconstructed image using the UD acquisition scheme (AL=0.84). A 2D ANOVA found a statistically significant difference (p=0.038) at a significance level of 0.05. In the current study, although a reconstructed image was also available using the VD acquisition scheme, it was not used to assist the MC detection task which was done using the center projection alone. In the case of evaluation of detection accuracy of masses, the reconstruction with VD-DBT (AL=0.71) was compared to that obtained from the UD-DBT (AL=0.78). The authors found no statistically significant difference between the two (p-value=0.22), although all the observers performed better for UD-DBT.

Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth.

OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome. METHODS: A nested, case-control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10-14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls. Associations were quantified as the odds ratio for a one decile increase in the corrected level of the analyte. RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88-0.96), extreme (24-32 weeks) spontaneous preterm birth (OR 0.90, 95% CI 0.83-0.99), moderate (33-36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88-0.98), and stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61-0.95). Higher levels of PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90-0.99) and delivery of a small for gestational age infant (OR 0.95, 95% CI 0.91-0.99). Associations were minimally affected by adjustment for maternal characteristics. CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk of adverse perinatal outcome.

Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth.

The risk of adverse perinatal outcome among 8839 women recruited to a multicenter, prospective cohort study was related to maternal circulating concentrations of trophoblast-derived proteins at 8-14 wk gestation. Women with a pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile at 8-14 wk gestation had an increased risk of intrauterine growth restriction [adjusted odds ratio, 2.9; 95% confidence interval (CI), 2.0-4.1], extremely premature delivery (adjusted odds ratio, 2.9; 95% CI, 1.6-5.5), moderately premature delivery (adjusted odds ratio, 2.4; 95% CI, 1.7-3.5), preeclampsia (adjusted odds ratio, 2.3; 95% CI, 1.6-3.3), and stillbirth (adjusted odds ratio, 3.6; 95% CI, 1.2-11.0). The strengths of the associations were similar when the test was performed before 13 wk gestation or between 13 and 14 wk gestation. In contrast, levels of free beta-human CG, another circulating protein synthesized by the syncytiotrophoblast, were not predictive of later outcome in multivariate analysis. PAPP-A has been identified as a protease specific for IGF binding proteins. We conclude that control of the IGF system in the first and early second trimester trophoblast may have a key role in determining subsequent pregnancy outcome.

Relationship of the platelet glycoprotein PlA and fibrinogen T/G+1689 polymorphisms with peripheral arterial disease and ischaemic heart disease.

INTRODUCTION: Genetic variation in plasma fibrinogen and the platelet receptor GP IIIa locus has been independently associated with increased risks of ischaemic heart disease, but there have been few reports on the relationship with peripheral arterial disease. This study determined the risk of peripheral arterial disease and ischaemic heart disease associated with polymorphisms of fibrinogen T/G(+1689) and platelet glycoprotein Pl(A) genes and the effects of cigarette smoking and fibrinogen. MATERIALS AND METHODS: In the 5-year follow-up phase of the Edinburgh Artery Study, 939 subjects (60-79 years) had DNA extracted from a venous blood sample. One hundred sixteen subjects were identified as having angina, 87 a myocardial infarction, 104 had intermittent claudication and 663 subjects comprised a healthy group. RESULTS: Distribution of the fibrinogen genotype was similar across the disease and healthy groups. Logistic regression analyses found no significant association between fibrinogen genotype and ischaemic heart disease and peripheral arterial disease. A lower percentage of claudicants had the Pl(A2) allele (8.3% vs. 15.2%, p=0.025). After adjustment for age and sex, the risk of IC associated with the Pl(A2) was half that of the homozygous Pl(A1) genotype (OR 0.49, 95% CI 0.25, 0.88; p<==0.05). Adjustment for lifetime smoking and fibrinogen levels increased the odds slightly to nonsignificance. CONCLUSIONS: The Pl(A2) genotype was associated with a decreased risk of developing IC. There was no significant relationship between fibrinogen T/G(+1689) genotype and ischaemic and peripheral heart disease in this older population.

First-trimester placentation and the risk of antepartum stillbirth.

CONTEXT: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. OBJECTIVE: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. MAIN OUTCOME MEASURES: Antepartum stillbirths and stillbirths due to specific causes. RESULTS: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk. CONCLUSION: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

A method to synchronize signals from multiple patient monitoring devices through a single input channel for inclusion in list-mode acquisitions.

PURPOSE: This technical note documents a method that the authors developed for combining a signal to synchronize a patient-monitoring device with a second physiological signal for inclusion into list-mode acquisition. Our specific application requires synchronizing an external patient motion-tracking system with a medical imaging system by multiplexing the tracking input with the ECG input. The authors believe that their methodology can be adapted for use in a variety of medical imaging modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET). METHODS: The authors insert a unique pulse sequence into a single physiological input channel. This sequence is then recorded in the list-mode acquisition along with the R-wave pulse used for ECG gating. The specific form of our pulse sequence allows for recognition of the time point being synchronized even when portions of the pulse sequence are lost due to collisions with R-wave pulses. This was achieved by altering our software used in binning the list-mode data to recognize even a portion of our pulse sequence. Limitations on heart rates at which our pulse sequence could be reliably detected were investigated by simulating the mixing of the two signals as a function of heart rate and time point during the cardiac cycle at which our pulse sequence is mixed with the cardiac signal. RESULTS: The authors have successfully achieved accurate temporal synchronization of our motion-tracking system with acquisition of SPECT projections used in 17 recent clinical research cases. In our simulation analysis the authors determined that synchronization to enable compensation for body and respiratory motion could be achieved for heart rates up to 125 beats-per-minute (bpm). CONCLUSIONS: Synchronization of list-mode acquisition with external patient monitoring devices such as those employed in motion-tracking can reliably be achieved using a simple method that can be implemented using minimal external hardware and software modification through a single input channel, while still recording cardiac gating signals.

Generation of voxelized breast phantoms from surgical mastectomy specimens.

PURPOSE: In the research and development of dedicated tomographic breast imaging systems, digital breast object models, also known as digital phantoms, are useful tools. While various digital breast phantoms do exist, the purpose of this study was to develop a realistic high-resolution model suitable for simulating three-dimensional (3D) breast imaging modalities. The primary goal was to design a model capable of producing simulations with realistic breast tissue structure. METHODS: The methodology for generating an ensemble of digital breast phantoms was based on imaging surgical mastectomy specimens using a benchtop, cone-beam computed tomography system. This approach allowed low-noise, high-resolution projection views of the mastectomy specimens at each angular position. Reconstructions of these projection sets were processed using correction techniques and diffusion filtering prior to segmentation into breast tissue types in order to generate phantoms. RESULTS: Eight compressed digital phantoms and 20 uncompressed phantoms from which an additional 96 pseudocompressed digital phantoms with voxel dimensions of 0.2 mm(3) were generated. Two distinct tissue classification models were used in forming breast phantoms. The binary model classified each tissue voxel as either adipose or fibroglandular. A multivalue scaled model classified each tissue voxel as percentage of adipose tissue (range 1%-99%). Power spectral analysis was performed to compare simulated reconstructions using the breast phantoms to the original breast specimen reconstruction, and fits were observed to be similar. CONCLUSIONS: The digital breast phantoms developed herein provide a high-resolution anthropomorphic model of the 3D uncompressed and compressed breast that are suitable for use in evaluating and optimizing tomographic breast imaging modalities. The authors believe that other research groups might find the phantoms useful, and therefore they offer to make them available for wider use.

Penalized maximum likelihood reconstruction for improved microcalcification detection in breast tomosynthesis.

We examined the application of an iterative penalized maximum likelihood (PML) reconstruction method for improved detectability of microcalcifications (MCs) in digital breast tomosynthesis (DBT). Localized receiver operating characteristic (LROC) psychophysical studies with human observers and 2-D image slices were conducted to evaluate the performance of this reconstruction method and to compare its performance against the commonly used Feldkamp FBP algorithm. DBT projections were generated using rigorous computer simulations that included accurate modeling of the noise and detector blur. Acquisition dose levels of 0.7, 1.0, and 1.5 mGy in a 5-cm-thick compressed breast were tested. The defined task was to localize and detect MC clusters consisting of seven MCs. The individual MC diameter was 150 µm. Compressed-breast phantoms derived from CT images of actual mastectomy specimens provided realistic background structures for the detection task. Four observers each read 98 test images for each combination of reconstruction method and acquisition dose. All observers performed better with the PML images than with the FBP images. With the acquisition dose of 0.7 mGy, the average areas under the LROC curve (A(L)) for the PML and FBP algorithms were 0.69 and 0.43, respectively. For the 1.0-mGy dose, the values of A(L) were 0.93 (PML) and 0.7 (FBP), while the 1.5-mGy dose resulted in areas of 1.0 and 0.9, respectively, for the PML and FBP algorithms. A 2-D analysis of variance applied to the individual observer areas showed statistically significant differences (at a significance level of 0.05) between the reconstruction strategies at all three dose levels. There were no significant differences in observer performance for any of the dose levels.

Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study.

OBJECTIVE: To evaluate the use of ultrasound measurements of fetal nuchal translucency (NT) obtained in a routine antenatal clinic setting in combination with appropriate biochemical markers as a first trimester screening test for Down's Syndrome. DESIGN: Multicentre observational study. SETTING: Fifteen Scottish maternity units. POPULATION: Pregnant women (n = 17,229) attending routine antenatal clinics at 10-14 weeks of gestation. METHODS: NT measurements were attempted in all women along with the measurement of maternal serum free beta human chorionic gonadotrophin (F beta hCG) and pregnancy-associated plasma protein-A (PAPP-A). All results were converted to multiples of the appropriate gestational median (MoM) and using a statistical model the risk of an affected pregnancy was derived. No results were given to participating women but all were offered routine second trimester biochemical screening. All cases of Down's Syndrome within the study group were ascertained and the detection rate for each marker was estimated. MAIN OUTCOME MEASURES: Success rate of obtaining NT measurements and overall effectiveness of ultrasound and biochemical markers individually and in combination for the detection of Down's Syndrome pregnancies. RESULTS: NT measurements were obtained in 72.9% of women and blood samples in 98.4%. Forty-five cases of Down's Syndrome were ascertained (2.6/1,000). NT measurements were obtained in 37 cases (median NT 1.65 MoM), blood samples in 42 cases and both NT and blood in 34 cases. In combination with the a priori maternal age risk, observed detection rates at a 5% false positive rate were 20/37 (54%) for NT, 23/42 (55%) for F beta hCG and PAPP-A and 28/34 (82%) for a combination of NT, F beta hCG and PAPP-A using a cutoff risk of 1:250. The effect of failing to obtain NT measurements in all cases reduces the overall detection rate to 62% (i.e. 28/45) if the entire series of affected pregnancies within the study group is considered. CONCLUSIONS: NT in combination with appropriate serum markers has the potential to detect over 80% of Down's Syndrome fetuses in early pregnancy. However, NT measurement is highly operator-dependent. It requires training, external quality control and adequate time to allow accurate measurement, otherwise suboptimal performance will result.