Automated analysis of rabbit knee calcified cartilage morphology using micro-computed tomography and deep learning

Structural dynamics of calcified cartilage (CC) are poorly understood. Conventionally, CC structure is analyzed using histological sections. Micro-computed tomography (µCT) allows for three-dimensional (3D) imaging of mineralized tissues; however, the segmentation between bone and mineralized cartilage is challenging. Here, we present state-of-the-art deep learning segmentation for µCT images to assess 3D CC morphology. The sample includes 16 knees from 12 New Zealand White rabbits dissected into osteochondral samples from six anatomical regions: lateral and medial femoral condyles, lateral and medial tibial plateaus, femoral groove, and patella (n = 96). The samples were imaged with µCT and processed for conventional histology. Manually segmented CC from the images was used to train segmentation models with different encoder–decoder architectures. The models with the greatest out-of-fold evaluation Dice score were selected. CC thickness was compared across 24 regions, co-registered between the imaging modalities using Pearson correlation and Bland–Altman analyses. Finally, the anatomical CC thickness variation was assessed via a Linear Mixed Model analysis. The best segmentation models yielded average Dice of 0.891 and 0.807 for histology and µCT segmentation, respectively. The correlation between the co-registered regions was strong (r = 0.897, bias = 21.9 µm, standard deviation = 21.5 µm). Finally, both methods could separate the CC thickness between the patella, femoral, and tibial regions (p < 0.001). As a conclusion, the proposed µCT analysis allows for ex vivo 3D assessment of CC morphology. We demonstrated the biomedical relevance of the method by quantifying CC thickness in different anatomical regions with a varying mean thickness. CC was thickest in the patella and thinnest in the tibial plateau. Our method is relatively straightforward to implement into standard µCT analysis pipelines, allowing the analysis of CC morphology. In future research, µCT imaging might be preferable to histology, especially when analyzing dynamic changes in cartilage mineralization. It could also provide further understanding of 3D morphological changes that may occur in mineralized cartilage, such as thickening of the subchondral plate in osteoarthritis and other joint diseases.     

Contesting lifestyle risk and gendering coronary candidacy: lay epidemiology of heart disease in Finland in the 1970s

This study addresses two issues currently under critical discussion in the epidemiology of cardiovascular diseases (CVD), the relative neglect of women and the individualised nature of key risk factors. It focuses on the North Karelia project (NKP), a community programme aimed at coronary heart disease (CHD) prevention in a predominantly rural Finnish region in the early 1970s, that is, during a period when the epidemiological understanding of CVD still was relatively new and actively promoted. Adopting the notions of lay epidemiology and coronary candidacy, culturally mediated explanatory models lay people use to assess who is likely to develop heart disease and why, the study shows that locals targeted by the project critically engaged with both of these bias. Based on the rich materials resulting from project activities the study shows, first, how many locals subsumed the individualised and lifestyle‐based approach to CHD prevention promoted by NKP under a more general framework emphasising the health effects of ongoing structural changes in the area, and second, how women constructed themselves as viable coronary candidates. The case supports the position in the current discussions on lay expertise that wants to integrate lay experiences more firmly into epidemiological studies and public health.     

First trimester combined screening biochemistry in detection of congenital heart defects

Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fβ-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs).

Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down’s syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland.

Results: Both PAPP-A and fβ-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fβ-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fβ-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively.

Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fβ-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans.     

Genetics of inflammation and atopy

Multiple chromosomal regions and polymorphisms of several candidate genes have been linked to or associated with atopic diseases (hayfever, asthma, allergic eczema and rhinitis). In this mini-review, we present data demonstrating that the genetic regulation of the inflammatory response makes a major contribution to the risk of atopy. These data also suggest that the quantity (or quality) of the inflammation affects the priming phase of atopy, i.e., that induced by allergens or infectious agents in early childhood.     

Sex hormone-binding globulin and insulin-like growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovascular risk, and mortality in elderly men

Two binding proteins, SHBG and IGF-binding protein-1 (IGFBP-1), are both down-regulated by insulin and therefore could serve as potential indicators of the metabolic syndrome and hyperinsulinemia-related cardiovascular risk. We compared serum SHBG and IGFBP-1 as potential markers of abnormal glucose tolerance, the metabolic syndrome, diabetes mellitus, cardiovascular risk factors, and total, cardiovascular, and coronary heart disease mortality in elderly men. Of the original cohort of 1711 men, 524 were alive on January 1, 1989, and 413 participated in the 30-yr examination, of whom 335 men, aged 70-89 yr, formed the study group for the present analysis. Low SHBG and IGFBP-1 were both associated with an increased prevalence of abnormal glucose tolerance and the metabolic syndrome, but only SHBG was associated with diabetes mellitus. SHBG was less influenced by body mass index than IGFBP-1. Low SHBG indicated increased cardiovascular and coronary disease mortality; the association remained after adjustment for abnormal glucose tolerance, but not after adjustment for prevalent cardiovascular disease. IGFBP-1 had no association with mortality. It is concluded that low SHBG is a better indicator of increased cardiovascular mortality than low or high IGFBP-1.     

Increased carotid atherosclerosis in andropausal middle-aged men

OBJECTIVES: This study examined the association between carotid artery intima-media thickness (IMT), serum sex hormone levels, and andropausal symptoms in middle-aged men. BACKGROUND: Male sex hormones may play a dual role in the pathogenesis of atherosclerosis in men by carrying both proatherogenic and atheroprotective effects. METHODS: We studied 239 40- to 70-year-old men (mean +/- SD: 57 +/- 8 years) who participated in the Turku Aging Male Study and underwent serum lipid and sex hormone measurements. Ninety-nine men (age 58 +/- 7 years) were considered andropausal (i.e., serum testosterone <9.8 nmol/l or luteinizing hormone [LH] >6.0 U/l and testosterone in the normal range), and in both situations, they had subjective symptoms of andropause (a high symptom score in questionnaire). Three were excluded because of diabetes. The rest of the men (age 57 +/- 8 years) served as controls. Carotid IMT was determined using high-resolution B-mode ultrasound, and serum testosterone, estradiol (E2), LH, and sex hormone-binding globulin were measured using standard immunoassays. RESULTS: Andropausal men had a higher maximal IMT compared with controls in the common carotid (1.08 +/- 0.34 vs. 1.00 +/- 0.23, p < 0.05) and in the carotid bulb (1.44 +/- 0.48 vs. 1.27 +/- 0.35, p = 0.003). Common carotid IMT correlated inversely with serum testosterone (p = 0.003) and directly with LH (p = 0.006) in multivariate models adjusted for age, total cholesterol, body mass index, blood pressure, and smoking. CONCLUSIONS: Middle-aged men with symptoms of andropause, together with absolute or compensated (as reflected by high normal to elevated LH) testosterone deficiency, show increased carotid IMT. These data suggest that normal testosterone levels may offer protection against the development of atherosclerosis in middle-aged men.     

Effect of carboxylesterase 1 c.428G?>?A single nucleotide variation on the pharmacokinetics of quinapril and enalapril

Aim

The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers.

Methods

In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h.

Results

The area under the plasma concentration–time curve from 0 h to infinity (AUC_0–∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC_0–∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril.

Conclusions

The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.