Keloids: The paradigm of skin fibrosis - Pathomechanisms and treatment.

Keloids, fibroproliferative dermal tumors with effusive accumulation of extracellular matrix (ECM) components, particularly collagen, result from excessive expression of growth factors and cytokines. The etiology of keloids is unknown but they occur after dermal injury in genetically susceptible individuals, and they cause both physical and psychological distress for the affected individuals. Several treatment methods for keloids exist, including the combination therapy of surgical excision followed by intralesional steroid therapy, however, they have high recurrence rate regardless of the current treatment method. Improved understanding of the pathomechanisms leading to keloid formation will hopefully identify pathways that serve as specific targets to improve therapy for this devastating, currently intractable, disorder.

Keloids: Animal models and pathologic equivalents to study tissue fibrosis.

Animal models are crucial for the study of fibrosis. Keloids represent a unique type of fibrotic scarring that occurs only in humans, thus presenting a challenge for those studying the pathogenesis of this disease and its therapeutic options. Here, several animal models of fibrosis currently in use are described, emphasizing recent progress and highlighting encouraging challenges.

Combination of PAPPA, fhCGß, AFP, PlGF, sTNFR1, and Maternal Characteristics in Prediction of Early-onset Preeclampsia.

OBJECTIVE: To evaluate the efficacy of first-trimester markers-pregnancy-associated plasma protein A (PAPPA), free human chorionic gonadotropin ß (fhCGß), alpha-fetoprotein (AFP), placental growth factor (PlGF), and soluble tumor necrosis factor receptor-1 (sTNFR1) together with maternal characteristics (MC) for prediction of early-onset preeclampsia (EOPE). METHODS: During 2005-2010, the abovementioned biomarkers were analyzed with logistic regression analysis in 64 EOPE and 752 control subjects to determine whether these biomarkers separately and in combination with MC would predict development of EOPE. RESULTS: PAPPA, fhCGß, and PlGF levels were lower, whereas AFP and sTNFR1 levels were higher in mothers with EOPE compared to controls. The combination of all markers with MC (age, weight, and smoking status) detected 48% of the mothers with EOPE, with a 10% false-positive rate (FPR). CONCLUSIONS: First-trimester maternal serum levels of PAPPA, fhCGß, AFP, PlGF, and sTNFR1, together with MC, are predictive of development of subsequent EOPE. These markers, along with MC, form a suitable panel for predicting EOPE.

First trimester placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in the prediction of early-onset severe pre-eclampsia.

OBJECTIVE: In a retrospective case-control study, we examined the levels of placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in first-trimester maternal serum samples as well as maternal characteristics to predict early-onset and severe pre-eclampsia. METHODS: In this retrospective case-control study, we identified females who delivered a singleton pregnancy on or after 24 weeks' gestation from 2003 to 2010 at Oulu University Hospital and had a retrospective first trimester trisomy screening, including serum PAPP-A measurement. Within this cohort, we identified 65 females who experienced early onset pre-eclampsia (EO-PE) and 742 controls who had uncomplicated deliveries. Retrospectively, we thawed all previously collected serum samples to measure placental retinol binding protein 4 (RBP4). PAPP-A and RBP4 were measured using automatic immunoassay systems and converted to multiples of the median (MoMs). Logistic regression analysis was performed to determine whether these biomarkers separately and in combination with maternal characteristics (maternal age, weight and smoking status) can be used to predict the development of early onset pre-eclampsia. RESULTS: The expected log(10) PAPP-A concentration and the expected log(10) RBP4 concentration in the control group were both affected by maternal weight and smoking status. The expected log(10) PAPP-A concentration was also affected by gestational age (GA). RBP4 levels in first-trimester serum were significantly higher in females who subsequently developed EO-PE outcome compared to those with normal pregnancy outcome (1.14 vs. 1.01 MoMs, p<0.0001). Maternal serum PAPP-A levels from the same pregnancy period were significantly lower in the EO-PE group compared to controls (0.80 vs. 1.05 MoMs, p=0.005). The risk model including maternal characteristics with PAPP-A log(10) MoM and RBP4 log(10) MoM had the best EO-PE prediction ability. It detected 34% (23%-46%) of females with subsequent EO-PE with a 10% false positive rate. CONCLUSION: This study showed that first-trimester maternal serum RBP4 was significantly increased and that PAPP-A decreased in pregnancies that ended in EO-PE compared to normal pregnancies. Thus, these markers may be useful members in a panel of markers for the early detection of early-onset and severe pre-eclampsia.

Combined first-trimester screening in northern Finland: experiences of the first ten years.

OBJECTIVE: To evaluate the efficacy of first trimester combined screening for Down's syndrome in Northern Finland during the first 10 years of practice. METHODS: During 1 January 2002 to 31 December 2011, 47,896 women participated voluntarily in combined screening during first trimester. The risk cutoff was 1:250. The study period was divided into two time periods; 2002-2006 and 2007-2011. RESULTS: During the first half of the study period, the detection rate (DR) was 77.3% with a 4.9% false-positive rate (FPR). During the latter half, the DR was 77.1% with a 2.8% FPR. CONCLUSIONS: An important issue is the number of invasive procedures needed to detect one case of Down's syndrome. The screening performance improved markedly in the latter five years period since the FPR lowered from 4.9% to 2.8% and the number of invasive procedures needed to detect one case of Down's syndrome lowered from 15 to 11.

Serum hyperglycosylated human chorionic gonadotrophin at 14-17 weeks of gestation does not predict preeclampsia.

INTRODUCTION: Low first-trimester serum concentrations of hyperglycosylated human chorionic gonadotrophin (hCG-h) predict later preeclampsia. We studied whether serum hCG-h at 14-17 weeks of pregnancy also predicts preeclampsia alone or combined with placental growth factor (PlGF) and soluble vascular endothelial growth factor 1 (sVEGFR-1). METHODS: We conducted a nested case-control study comprising 55 women with subsequent preeclampsia, 21 with gestational hypertension, 30 with a small-for-gestational-age infant, and 83 controls. Serum concentrations of hCG-h, proportion of hCG-h to hCG (%hCG-h), PlGF, and sVEGFR-1 were converted to multiples of the medians (MoMs) adjusted for gestational age. RESULTS: Concentrations of hCG-h or %hCG-h did not differ between women with subsequent preeclampsia and controls. In women with subsequent preeclampsia, PlGF was lower (0.62 MoM) than in controls (P < 0.001). In receiver-operating characteristics curve analysis for the prediction of preeclampsia, the area under the curve for hCG-h or %hCG-h was not significantly different from 0.5, whereas that for PlGF was 0.746 (95% confidence interval, 0.656-0.836; P < 0.001). Combining hCG-h or %hCG-h with PlGF did not improve the prognostic value. CONCLUSIONS: Serum hCG-h did not improve prediction of preeclampsia in the second trimester.

Comparison of combined, biochemical and nuchal translucency screening for Down syndrome in first trimester in Northern Finland.

OBJECTIVE: To compare the efficacy of fetal nuchal translucency screening, maternal serum screening and combined screening for Down syndrome. DESIGN: A prospective study. SETTING: University hospital and its public health care district in Northern Finland. POPULATION: A total of 35,314 women participated in the first-trimester screening for Down syndrome within the public healthcare system in 2002-08. There were 95 pregnancies involving Down syndrome. Serum samples were obtained from 35,314 women, nuchal translucency was measured in 27,144 pregnancies and full combined screening was performed in those pregnancies, including 76 involving Down syndrome. METHODS: The adjusted estimated risk for Down syndrome was calculated using the Perkin Elmer AutoDELFIA® time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free ß-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel in a university or district hospital. Risk cut-off figures 1:250 and 1:300 at term were used. MAIN OUTCOME MEASURES: Differences in detection rate, false-positive rate, positive and negative predictive values between nuchal translucency screening, serum screening and combined screening. RESULTS: Using the risk cut-off figure 1:250, the detection rates for serum screening, nuchal translucency screening and combined screening were 64.2, 64.5 and 72.4%, respectively and the false-positive rates were 7.8, 4.4 and 4.0%, respectively. CONCLUSIONS: Combined screening is the method of choice for Down syndrome screening in Finland.

First trimester Down syndrome screening is less effective and the number of invasive procedures is increased in women younger than 35 years of age.

OBJECTIVES: We evaluated the performance of first trimester screening for Down syndrome in women less than 35 years of age (study group) and in women aged 35 years or more (control group) in an unselected low-risk population. METHODS: The study group comprised a total of 63,945 women who participated in the first trimester combined screening in public health care in Finland during the study period of 1 May 2002 to 31 December 2008. Women at the age of 35 or more (n = 13,004) were controls. Prevalence of Down syndrome, detection rate, false positive rate and number of invasive procedures needed to detect a single case of Down syndrome were analyzed in both groups. RESULTS: The overall prevalence of Down syndrome (n = 73) in the study group was 1:876. The number of detected cases was 54. The detection rate was 74.0% with a false positive rate of 2.8%. Number of invasive procedures needed to detect a single case of Down syndrome was 33. In the control group, the detection rate was 87.0% with a false positive rate of 11.9%. The number of invasive procedures needed to detect a single case of Down syndrome was 15. The differences in detection rate and false positive rate were significant, P < 0.012, P < 0.001, respectively. CONCLUSION: The overall detection rate given for the entire population is an overestimate for a woman younger than the age of 35, which should be taken into consideration when counselling women of that age.

Adding ADAM12 in risk calculation program does not improve the detection rate of trisomies 18 and 13 in first trimester screening.

OBJECTIVE: To investigate first trimester levels of ADAM12 in trisomy 18 and 13 pregnancies and whether incorporating ADAM12 in the LifeCycle™ risk calculation program of trisomy 18 and trisomy 13 screenings can improve the detection rates of trisomies 18 and 13. METHODS: ADAM12 was incorporated in the LifeCycle™ risk calculation program. A specific algorithm with cut-off of 1:200 for screening of trisomies 18 and 13 was employed. Detection rates for trisomies 18 and 13 were calculated. RESULTS: There was a significant difference in ADAM12 levels between trisomy 18 pregnancies and controls during the gestation weeks 9 + 0 - 10 + 6, but not thereafter. In trisomy 13 pregnancies there was no difference in weeks 9 + 0 - 10 + 6, but there was in 11 + 0 - 12 + 6. The specific algorithms for trisomies 18 and 13 combined with algorithm for trisomy 21 yielded detection rates of 73.7% and 66.7%, respectively. The combined false positive rate was 4.6%. Adding ADAM12, the detection rate for trisomy 18 was the same, at 73.7% and for trisomy 13, at 66.7%. CONCLUSION: ADAM12 did not improve the detection rate.

False-negative results in routine combined first-trimester screening for down syndrome in Finland.

We analyzed the frequency and possible causes of false-negative (Fn) screening results in first-trimester combined Down syndrome screening in Finland. During the study period (May 1, 2002, to December 31, 2008), 76,949 voluntary women with singleton pregnancies participated in screening. Maternal age at screening, week of gestation, levels of pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (fß-hCG), and nuchal translucency (NT) measurement were compared and statistically analyzed between true-positive (Tp) and Fn cases. There were a total of 188 Down syndrome cases (1:409) in the screened population; 154 confirmed Tp and 34 Fn cases. Most Fn cases (n = 25) occurred at 12 + 0 to 13 + 6 weeks' gestation and only nine Fn cases presented between 10 and 11 weeks' gestation. According to the logistic regression analysis, the NT measurement was the most powerful discriminating factor in Fn screening results and accounted for 37.2% of Fn results. The second most important factor was fß-hCG, adding 14.0% to R(2), followed by PAPP-A, which contributed a further 14.3%. The chosen parameters explain 83.9% of Fn results, but 16.1% remain due to unknown factor(s). All investigated parameters contributed to Fn screening results, but fetal NT was the most discriminating factor leading to an Fn screening result.

First trimester biochemistry at different maternal ages.

BACKGROUND: The performance of first trimester biochemical screening was compared at different pregnancy weeks and maternal ages during 2002-2008 in a screened population of 76,949 women. METHODS: The detection rates, as well as the median multiples of a median (MOMs) of free ß-human chorionic gonadotropin (free ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A), were compared between completed gestational weeks 8-13 and between different maternal ages separated into 5-year groupings. RESULTS: The number of singleton Down syndrome pregnancies was 221. The median age of the screened women was 30 years and the proportion of women aged ≥ 35 years 16.9%. The median age of the women with a Down syndrome pregnancy was 37 years. In women aged <35 years, the biochemical markers provided a detection rate of only 38.6%, whereas in women aged ≥ 35 years, the biochemical markers detected 82.7% of cases (p<0.01). CONCLUSIONS: Biochemical screening works best amongst women aged ≥ 35 years. For younger mothers aged <35 years, combined screening should be the method of choice.

Screening and outcome of chromosomal abnormalities other than trisomy 21 in Northern Finland.

OBJECTIVE: To examine the performance of first-trimester combined screening after adding the specific algorithms for trisomies 18 and 13 in the Down syndrome screening program for chromosomal abnormalities other than trisomy 21 and to determine the outcomes of such pregnancies. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. POPULATION: Pregnant women (n=56 076) participating voluntarily in first-trimester combined Down syndrome screening in Northern and Eastern Finland during the study period 1 June 2002 to 31 December 2008. METHODS: The data of all known cases of chromosomal abnormalities other than trisomy 21 were collected. MAIN OUTCOME MEASURES: Risk algorithms for trisomies 21, 18 and 13 were used for the calculation of patient-specific risks for certain chromosomal abnormalities. Algorithms were based on maternal age, crown-rump length, nuchal translucency, and measurement of free ß-human chorionic gonadotrophin and pregnancy-associated plasma protein-A. Detection rates and false-positive rates were calculated. RESULTS: A total of 27 cases of trisomy 18, 11 cases of trisomy 13 and 30 cases of other chromosomal abnormalities were analyzed. The algorithm for Down syndrome detected 55.6% of trisomy 18 cases, 36.4% of trisomy 13 cases and 60.0% of other chromosomal abnormalities. When specific risk algorithms were added, the detection rates improved for trisomy 18 (74.0%) and for trisomy 13 (54.5%), with only a slight increase of the false-positive rate of 0.2%. The detection rate for other chromosomal abnormalities did not improve. CONCLUSIONS: Adding the trisomy 18 algorithm to the Down screening program resulted in the detection of five additional trisomy 18 cases.

More invasive procedures are done to detect each case of Down's syndrome in younger women.

OBJECTIVE: To evaluate the performance of first-trimester combined screening in 5-year periods according to maternal age in a low-risk population. DESIGN: A prospective study. SETTING: Multicenter study in Finland. POPULATION: A total of 76949 voluntary women with singleton pregnancies participated in first-trimester combined screening in public healthcare between 1 May 2002 and 31 December 2008. METHODS: The serum samples were analyzed using the PerkinElmer AutoDELFIA® time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel (midwives or physicians) in a university or central hospital. MAIN OUTCOME MEASURES: Performance, detection rate, false positive rate and the number of invasive procedures needed to detect a single case of Down's syndrome were analyzed. RESULTS: There was a direct connection between maternal age and the prevalence of Down's syndrome with a low prevalence in young women being 1:1 193 in the 25-29 age group and 1:150 in the 35-39 age group. Consequently, for a fixed false positive rate of 5%, the number of invasive procedures needed to detect one case of Down's syndrome is higher in younger women to achieve the same detection rate. CONCLUSIONS: In combined first trimester screening the risk for Down's syndrome is individual, varying with maternal age. This should be taken into consideration when counseling women.

Low maternal PAPP-A is associated with small-for-gestational age newborns and stillbirths.

We investigated the association of first trimester low maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels with small-for-gestational age (SGA) newborns and stillbirths (SBs) in a retrospective national population-based register study. The study group comprised 921 women with the lowest 5% PAPP-A levels (< or =0.3 MoM) and the control group comprising 18,615 women with PAPP-A levels >0.3 MoM. In the study group there were 35 (3.8%) and in the control group 213 SGA newborns (1.1%), respectively (OR, 3.41; 95% CI, 2.37-4.91). There were 9 (1.0%) and 51 (0.3%) cases of SBs in the study and control groups, respectively (p < 0.002; OR, 3.59; 95% CI, 1.76-7.32). Low PAPP-A is a risk factor for SGA and SB.

Prevalence of Down's syndrome in a pregnant population in Finland.

The characteristics of the Finnish parturient have changed in recent years. The mean age of mothers at first delivery is now 29.3 years and the number of women > 35 years of age has increased to 19%. This shift has led to an increase in the prevalence of Down's syndrome. Between 1 January 2002 and 31 December 2006, there were 795 cases of Down's syndrome (27/10,000) in the Finnish Register of Congenital Malformations. The distribution of Down's syndrome in terminated pregnancies and newborns was analyzed in 5-year periods based on maternal age. The distribution of Down's syndrome cases in younger women (< 35 years) and in older women (> or =35 years) at the time of delivery was compared. The majority of new Down's syndrome cases occurred in the group having older women (61.1%), even though 35 years is the arbitrary threshold.