Ontogenic changes in placental transthyretin

Objectives

Before secretion of fetal thyroid hormone at around 16 weeks gestation normal fetal development depends on a constant supply of maternal thyroid hormone (TH), particularly thyroxine (T₄). The detailed mechanisms of transplacental delivery of TH are still uncertain. The TH binding protein, transthyretin (TTR), is produced and secreted by placenta and may play a role in this process. The ontogeny of placental TTR is unknown. Our aim was to study changes in placental TTR in early and late pregnancy.

Study design

We collected placentas from surgically terminated pregnancies between 6 and 17 weeks gestation (n = 44) and from normal term (38-39 weeks) pregnancies following caesarean section (n = 5). Real time-PCR, western blotting and immunohistochemistry were used to determine TTR mRNA and protein levels.

Results

There were highly significant correlations between gestational age and TTR mRNA (r = 0.974; p < 0.0001) and between gestational age and TTR protein (r = 0.901; p < 0.001) levels between weeks 6 and 13 of gestation. TTR expression did not increase between 13 and 17 weeks and was not different at term. Good correlation was observed between TTR mRNA and TTR protein between individual placental samples (r = 0.916; p < 0.0001). A similar trend was observed using immunohistochemical staining of placental paraffin sections.

Conclusions

Our results demonstrate that TTR is expressed in the human placenta from at least 6 weeks gestation. Levels rise during the first trimester at a time when placental oxygen tensions are also rising. We hypothesise that TTR production and secretion by the placenta may facilitate transplacental delivery of TH to the fetus.     

Oxygen concentration regulates expression and uptake of transthyretin, a thyroxine binding protein, in JEG-3 choriocarcinoma cells

Maternal thyroid hormone is provided to the fetus before the onset of fetal thyroid function (at about 16 weeks) and is essential for normal neurologic development. Mechanisms of transport are uncertain but transthyretin (TTR), a thyroxine binding protein produced by the placenta may be involved. Placental oxygen concentrations in early pregnancy are low, about 1% early in the first trimester and rising to 8% over the next 12 weeks. This study investigated the regulation of TTR expression, secretion and uptake in JEG-3 placental cells cultured at different oxygen concentrations. TTR mRNA and protein expression and ¹²⁵I-TTR and Alexa-Fluor594-TTR uptake were significantly higher in cells cultured at 1% and 3% O₂, than at 8% O₂. This suggests that increased carrier mediated T₄ transport by placental TTR may be induced by the low oxygen environment of early pregnancy, a time when the fetus has its highest requirement for transport of maternal T₄.     

Ovarian cancer risk assessment: a tool for preoperative assessment

Objectives

The objective of this pilot study was to determine if the combination of CA 125, menopausal status and prealbumin can be used to accurately predict ovarian cancer in women with pelvic masses.

Study design

Preoperative serum CA 125, prealbumin and menopausal status were prospectively determined. Results were formulated into an ovarian cancer risk assessment (OCRA) score and compared with final surgical pathology.

Results

OCRA was studied in 130 women. No cancers were found in women with a score less than 200. For all cancers, an OCRA score ≥ 200 had a sensitivity of 96%, specificity of 95% and positive predictive value of 95%. When the OCRA score of ≥200 was evaluated for its ability to predict ovarian cancer, the sensitivity, specificity, and positive predictive value were 100%, 83%, and 78%, respectively.

Conclusions

In this pilot study, OCRA was able to predict which women with pelvic masses were more likely to have ovarian cancer. The scoring system easily applied clinically and may help facilitate appropriate referral of women to gynecologic oncologists for optimal care.     

Left ventricular wall thickness and severity of cardiac disease in women and men with transthyretin amyloidosis

Aims

Cardiac amyloidosis (CA) is due to a deposition of amyloid fibrils in the heart causing an increase in wall thickness. A left ventricular (LV) wall thickness ≥12 mm plus at least one red flag should raise the suspicion of CA. As normal values of LV wall thickness are lower in women, the adoption or the same cut-off values for men and women could lead to underdiagnosis or delayed diagnosis in women. We investigated the relationship between LV wall thickness and the severity of cardiac involvement in women and men with transthyretin (ATTR) CA.

Methods and results

We evaluated 330 consecutive patients diagnosed with ATTR-CA at three centres (Pisa, n = 232; Brescia, n = 69; Trieste, n = 29). Interventricular septum (IVS) and posterior wall (PW) thickness values were lower in women (n = 53, 16%) than men, but most differences were abolished when indexing by body surface area (BSA), height, or height^2.7, suggesting similar disease severity when accounting for the smaller body size of women. PW thickness indexed for height^2.7 was even higher in women. We also searched for correlations between IVS and PW thickness and other indicators of the severity of cardiac disease. IVS values indexed by height^2.7 displayed tighter associations with N-terminal pro-B-type natriuretic peptide values than non-indexed IVS values. Similarly, indexed values displayed closer relationships with relative wall thickness, E/e' ratio, and tricuspid annular plane systolic excursion.

Conclusions

Indexed LV wall thickness values, particularly by height^2.7, reflect more accurately the severity of cardiac involvement than non-indexed values.     

类风湿关节炎患者血清转甲状腺素蛋白化学修饰的蛋白质组学分析

目的通过检测类风湿关节炎(RA)患者血清转甲状腺素蛋白(TTR)的化学修饰类型和含量,探讨其在RA早期诊断中的潜在作用。方法采用酶联免疫吸附试验(ELISA)测定39名RA患者[早期(<1年)16例,中晚期(>2年)23例]、20名骨性关节炎(OA)患者及20名健康体检者血清TTR含量;采用Western blot测定血清TTR分子聚合体比例;采用基质辅助激光解吸离子化飞行时间质谱(MALDI-TOF-MS)技术鉴定血清中TTR蛋白的化学修饰类型和比例。结果 RA早期患者血清TTR含量为(502.46±109.25)mg/L,明显高于正常对照组[(424.98±118.52)mg/L](P<0.05);RA中晚期患者[(440.67±94.15)mg/L]也有增高趋势,但与正常对照组比较差异无统计学意义(P=0.733);OA组TTR含量为(363.91±106.41)mg/L,与正常对照组比较差异无统计学意义(P=0.072)。血清TTR化学修饰有4种蛋白峰:质荷比(m/z)13 749.86±1.48、m/z 13 829.63±2.76、m/z 13 870.70±2.70、m/z 13 927±5.7...     

Length-dependent truncal Aδ-fiber dysfunction in hereditary transthyretin amyloidosis: An intra-epidermal electrical stimulation study

ObjectiveTo elucidate Aδ-fiber dysfunction at the trunk in patients with hereditary transthyretin (ATTRm) amyloidosis using intra-epidermal electrical stimulation (IES).MethodsIn 16 patients with ATTRm amyloidosis and 18 healthy subjects, sensory thresholds using IES and cooling detection thresholds using the Computer-Aided Sensory Evaluation (CASE IV) system, were assessed to investigate Aδ-fiber functions at the Th10 level of the anterior, lateral, and posterior trunk. Furthermore, evoked potentials (EPs) following electrical stimulation using IES at the anterior and posterior trunk were evaluated.ResultsIn patients with ATTRm amyloidosis, both IES and CASE IV sensory thresholds tended to be higher at the anterior trunk than at the lateral and posterior trunks. The amplitudes of EPs following electrical stimulation at the anterior trunk were lower than those at the posterior trunk. Aδ-fiber dysfunction at the anterior trunk was conspicuous in patients with more intense polyneuropathy at the limbs. In healthy subjects, there were no differences in both sensory thresholds and EP amplitudes among any examination sites. Sensory thresholds with IES and CASE IV were correlated.ConclusionsEvaluation using IES demonstrated length-dependent Aδ-fiber dysfunction at the trunk in patients with ATTRm amyloidosis.SignificanceIES may be a useful clinical tool for investigating Aδ-fiber dysfunction at various parts of the body in patients with neuropathy.     

Multi-modality imaging in transthyretin amyloid cardiomyopathy

Transthyretin amyloid(TTR) cardiomyopathy is a disease of insidious onset,which is often accompanied by debilitating neurological and/or cardiac complications. The true prevalence is not fully known due to its elusive presentation, being often under-recognized and usually diagnosed only late in its natural history and in older patients. Because of this, effective treatment options are usually precluded by multiple comorbidities and frailty associated with such patients. Therefore, high clinical suspicion with earlier and better detection of this disease is needed. In this review, the novel applications of multimodality imaging in the diagnostic pathway of TTR cardiomyopathy are explored. These include the complimentary roles of transthoracic echocardiography, cardiac magnetic resonance, nuclear scintigraphy and positron emission tomography in quantifying cardiac dysfunction, diagnosis and risk stratification. Recent advances in novel therapeutic options for TTR have further enhanced the importance of a timely and accurate diagnosis of this disease.