M Halit Pinar MD - Academia.edu (original) (raw)

Papers by M Halit Pinar MD

0\. Titelseite und Inhaltsverzeichnis 1\. Einleitung und Zielsetzung 5 1.1. Sepsis bei Erwachsene... more 0\. Titelseite und Inhaltsverzeichnis 1\. Einleitung und Zielsetzung 5 1.1. Sepsis bei Erwachsenen und Neugeborenen 5 1.2. Proteasen und deren Inhibitoren 8 1.3. Zielsetzung der Arbeit 12 2\. Material und Methoden 13 2.1. Chemikalien 13 2.2. Puffer 13 2.3. Allgemeine proteinchemische Verfahren 14 2.4. Elektrophoretische Verfahren 14 2.5. Färbemethoden 16 2.6. Immunologische Verfahren 16 2.7. Chromatographische Verfahren (HPLC) 20 3\. Ergebnisse 23 3.1. Charakterisierung der Antikörper gegen Inter-a-Inhibitor 23 3.2. Reinigung von IaI aus humanem Plasma 26 3.3. Entwicklung und Optimierung des Sandwich-ELISA 31 3.4. Quantifizierung von Inter-a-Inhibitor in Plasmaproben 35 4\. Diskussion 47 4.1. Methoden zur Etablierung des ELISA 47 4.2. Inter-a-Inhibitor als diagnostischer Marker bei neonataler Sepsis 49 5\. Zusammenfassung 53 6\. Literaturverzeichnis 55 7\. Anhang 55Zielsetzung: Aussagekräftige Tests werden benötigt, um eine Neugeborenensepsis zu erkennen und die Anzahl und Dauer unn...

Placenta, 2018

Placental surface area is often estimated using diameter measurements. However, as many placentas... more Placental surface area is often estimated using diameter measurements. However, as many placentas are not elliptical, we were interested in the validity of these estimates. We compared placental surface area from images for 491 singletons from the Stillbirth Collaborative Research Network (SCRN) Study (416 live births, 75 stillbirths) to estimates obtained using diameter measurements. Placental images and diameters were obtained from pathologic assessments conducted for the SCRN Study and images were analyzed using ImageJ software. On average, diameter-based measures underestimated surface area by -5.58% (95% confidence interval: -30.23, 19.07); results were consistent for normal and abnormal shapes. The association between surface area and birthweight was similar for both measures. Thus, diameter-based surface area can be used to estimate placental surface area.

American journal of perinatology, 2018

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in chole... more Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive syndrome caused by a defect in cholesterol biosynthesis with mutations in 7-dehydrocholesterol reductase (DHCR7). A total of 3% of Caucasians carry DHCR7 mutations, theoretically resulting in a homozygote frequency of 1/4000. However, SLOS occurs in only 1/20,000 to 60,000 live births. Our objective was to assess DHCR7 mutations in unexplained stillbirths. Prospective, multicenter, population-based case-control study of all stillbirths and a representative sample of live births enrolled in five geographic areas. Cases with stillbirth due to obstetric complications, infection, or aneuploidy, and those with poor quality deoxyribonucleic acid (DNA) were excluded. DNA was extracted from placental tissue stored at -80°C, and exons 3 to 9 of the DCHR7 gene were amplified, purified, and subjected to bidirectional sequencing to identify mutations. One-hundred forty four stillbirths were unexplained and had adequate DNA for analy...

Infectious diseases in obstetrics and gynecology, 2017

Introduction. To investigate whether maternal oral flora might be involved in intrauterine infect... more Introduction. To investigate whether maternal oral flora might be involved in intrauterine infection and subsequent stillbirth or neonatal death and could therefore be detected in fetal and neonatal postmortem bacterial cultures. Methods. This retrospective study of postmortem examinations from 1/1/2000 to 12/31/2010 was searched for bacterial cultures positive for common oral flora from heart blood or lung tissue. Maternal age, gestational age, age at neonatal death, and placental and fetal/neonatal histopathological findings were collected. Results. During the study period 1197 postmortem examinations (861 stillbirths and 336 neonatal deaths) were performed in our hospital with gestational ages ranging from 13 to 40+ weeks. Cultures positive for oral flora were identified in 24 autopsies including 20 pure and 8 mixed growths (26/227, 11.5%), found in 16 stillbirths and 8 neonates. Microscopic examinations of these 16 stillbirths revealed 8 with features of infection and inflammati...

Paediatric and Perinatal Epidemiology, 2013

Background-Accurate assignment of gestational age at time of fetal death is important for researc... more Background-Accurate assignment of gestational age at time of fetal death is important for research and clinical practice. An algorithm to estimate gestational age (GA) at fetal death was developed and evaluated. Methods-The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and postmortem data. The SCRN conducted a population-based case-control study of women with stillbirths and live births from 2006 to 2008 in five geographic catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed. Results-The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within two days before diagnosis and 47.6% within one week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was 1 or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA

American Journal of Perinatology Reports, 2013

Acinetobacter species are a group of bacterial microorganisms that have emerged as significant no... more Acinetobacter species are a group of bacterial microorganisms that have emerged as significant nosocomial pathogens, with Acinetobacter baumannii being the most frequently isolated species. Acinetobacter infections have attracted increasing attention during recent years because they are resistant to most antibiotics and can be found in both hospitalized patients and the community. The spectrum of clinical manifestations is broad. In general, A. baumannii mainly infects patients with impaired host defense, such as those who are in the intensive care units. 1 Although there are conflicting results regarding clinical outcomes from different clinical studies, it appears that A. baumannii infection is associated with increased mortality. 2,3 Patients in neonatal intensive care units (NICU) usually have medical conditions that are associated with impaired host defense or immune response, such as preterm and premature birth. These conditions make them vulnerable for A. baumannii infection. There are a few reports of outbreaks of A. baumannii in the NICU. 4,5 Although death of infected neonates was reported in some of the studies, so far there is no report in the literature of postmortem examination with perinatal death associated with cultures positive for A. baumannii. The effect of A. baumannii infection on pregnancy was rarely studied; so far there is only one case report regarding A. baumannii infection related to pregnancy. 6

Pediatric and Developmental Pathology, 2002

Invasive treatment modalities for severe chronic twin-to-twin transfusion syndrome (TTTS), such a... more Invasive treatment modalities for severe chronic twin-to-twin transfusion syndrome (TTTS), such as fetoscopic laser coagulation of communicating vessels, have revived the need for detailed studies of placental angioar-chitecture. We describe a practical placental vascular injection technique using alcohol-resistant tissue-staining dyes. Injection of color-coded gelatin-dye mixtures effectively delineated the intertwin vasculature, and allowed unequivocal macroscopic classification of vascular communications as artery-to-artery, vein-to-vein, or deep artery–to-vein anastomoses. The existence of deep artery–to-vein anastomoses was further confirmed by light microscopic demonstration of venous dye of one twin and arterial dye of the opposite twin within the same stem villus. Furthermore, the injection technique allowed determination of the caliber of the anastomoses, the direction of the artery-to-vein anastomoses, and the relative vascular territory of each twin. Documenting the vascu...

Pediatric and Developmental Pathology, 1998

Congenital malformations of the central nervous system (CNS) are among the most common anomalies,... more Congenital malformations of the central nervous system (CNS) are among the most common anomalies, but data on the incidence of CNS malformations in autopsy populations are scant. We examined 4122 autopsies between the years 1958 and 1995. There were 363 cases (8.8%) with CNS malformations; 235 were neonates and 128 stillborns. The overall gender ratio was 1:1, although more male neonates and more female stillborns had malformations. The body weights ranged from 24 to 6440 g. Neural tube defects were the most common types of malformations (45.5%) and included anencephaly, meningoencephalocele, meningocele/meningomyelocele, craniospinal rachischisis, and spina bifida occulta. The incidences of other malformations were: congenital hydrocephalus (12.4%), neuronal/glial proliferation disorders such as micro- and macrocephaly (8.8%), neuronal migration disorders (8.8%), prosencephalon growth disorders such as holoprosencephaly and arhinencephaly (8.5%), abnormalities of the midline struct...

Obstetrics & Gynecology, 2009

Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 s... more Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 stillbirths in the United States every year. The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop from October 22-24, 2007, to review the pathophysiology of conditions underlying stillbirth to define causes of death. The optimal classification system would identify the pathophysiologic entity initiating the chain of events that irreversibly led to death. Because the integrity of the classification is based on available pathologic, clinical, and diagnostic data, experts emphasized that a complete stillbirth workup should be performed. Experts developed evidence-based characteristics of maternal, fetal, and placental conditions to attribute a condition as a cause of stillbirth. These conditions include infection, maternal medical conditions, antiphospholipid syndrome, heritable thrombophilias, red cell alloimmunization, platelet alloimmunization, congenital malformations, chromosomal abnormalities including confined placental mosaicism, fetomaternal hemorrhage, placental and umbilical cord abnormalities including vasa previa and placental abruption, complications of multifetal gestation, and uterine complications. In all cases, owing to lack of sufficient knowledge about disease states and normal development, there will be a degree of uncertainty regarding whether a specific condition was indeed the cause of death.

Obstetrics & Gynecology, 2014

Objective-To compare placental lesions for stillbirth cases and live birth controls in a populati... more Objective-To compare placental lesions for stillbirth cases and live birth controls in a population-based study. Methods-Pathological examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. Results-Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate was present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births.

Obstetrics & Gynecology, 2014

OBJECTIVE-To compare illicit drug and smoking use in pregnancies with and without stillbirth. MET... more OBJECTIVE-To compare illicit drug and smoking use in pregnancies with and without stillbirth. METHODS-The Stillbirth Collaborative Research Network conducted a case-control study from March 2006 to September 2008, covering more than 90% of deliveries to residents of five a priori defined geographically diverse regions. The study attempted to include all stillbirths and representative liveborn controls. Umbilical cord samples from cases and controls were collected and frozen for subsequent batch analysis. Maternal serum was collected at delivery and batch analyzed for cotinine. RESULTS-For 663 stillbirth deliveries, 418 (63%) had cord homogenate and 579 (87%) had maternal cotinine assays performed. For 1,932 live birth deliveries, 1,050 (54%) had cord homogenate toxicology and 1,545 (80%) had maternal cotinine assays performed. A positive cord homogenate test for any illicit drug was associated with stillbirth (OR 1.94; 95% CI 1.16, 3.27). The most common individual drug was cannabis (OR 2.34; 95% CI 1.13, 4.81), although the effect was partially confounded by smoking. Both maternal self-reported smoking history and maternal serum cotinine levels were associated in a dose-response relationship with stillbirth. Positive serum cotinine < 3 ng/ml and no reported history of smoking (proxy for passive smoke exposure) also was associated with stillbirth (OR 2.06; 95% CI 1.24, 3.41). CONCLUSION-Cannabis, smoking, illicit drug use, and apparent exposure to secondhand smoke, separately or in combination, during pregnancy were associated with an increased risk of

New England Journal of Medicine, 2012

Background Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true ... more Background Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. Methods The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. Results In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P = 0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P = 0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P = 0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. Conclusions Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained.

The Journal of Pediatrics, 2003

Paediatric and perinatal epidemiology, 2011

The Stillbirth Collaborative Research Network (SCRN) has conducted a multisite, population-based,... more The Stillbirth Collaborative Research Network (SCRN) has conducted a multisite, population-based, case-control study, with prospective enrollment of stillbirths and livebirths at the time of delivery. This paper describes the general design, methods and recruitment experience. The SCRN attempted to enroll all stillbirths and a representative sample of livebirths occurring to residents of pre-defined geographical catchment areas delivering at 59 hospitals associated with five clinical sites. Livebirths <32 weeks gestation and women of African descent were oversampled. The recruitment hospitals were chosen to ensure access to at least 90% of all stillbirths and livebirths to residents of the catchment areas. Participants underwent a standardised protocol including maternal interview, medical record abstraction, placental pathology, biospecimen testing and, in stillbirths, post-mortem examination. Recruitment began in March 2006 and was completed in September 2008 with 663 women wit...

American Journal of Perinatology, 2011

The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes ... more The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.

American Journal of Perinatology, 2011

We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Netwo... more We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations.

American Journal of Obstetrics and Gynecology, 2014

OBJECTIVE-We sought to compare bile acids in women with and without stillbirth in a population-ba... more OBJECTIVE-We sought to compare bile acids in women with and without stillbirth in a population-based study. STUDY DESIGN-The Stillbirth Collaborative Research Network conducted a multisite, population-based case-control study of stillbirth (fetal deaths ≥20 weeks). Maternal sera were obtained at the time of enrollment and frozen at −80° until assay for bile acids. RESULTS-Assays were performed in 581 women with stillbirth and 1546 women with live births. Bile acid levels were slightly higher in women with stillbirth (geometric mean [95% confidence interval {CI}] = 3.2 [3.0-3.5]) compared to live births (2.9 [2.7-3.1], P = .0327). However, the difference was not significant after adjustment for baseline risk factors for stillbirth. The proportion of women with elevated levels (≥10 or ≥40 μmol/L) was similar in stillbirths and live births. Results were similar when the analysis was limited to subsets of stillbirths and live births. In women with stillbirths not associated with fetal anomalies or obstetric complications bile

PLoS Medicine, 2014

Background: Stillbirth is strongly related to impaired fetal growth. However, the relationship be... more Background: Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. Methods and Findings: We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (,10th percentile) or large for gestational age (LGA) (.90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (,5th and .95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Conclusions: Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.

Pathology of the Placenta, 2018

Atherosis, Acute atherosis, Hypertensive arteriopathy. Hypertrophic decidual vasculopathy, Mural ... more Atherosis, Acute atherosis, Hypertensive arteriopathy. Hypertrophic decidual vasculopathy, Mural hypertrophy of membrane arterioles. Membranous decidua, Parietal decidua, Decidua parietalis, Decidua attached to the placental membranes. 43.4 Epidemiology The prevalence of atherosis and mural hypertrophy in the placental membranes varies depending on the number of membrane sections. The literature suggests atherosis is seen in roughly 10-40% of pregnancies complicated by early-onset preeclampsia and is also seen, but less frequently,

Placenta, 2018

American journal of perinatology, 2018

Infectious diseases in obstetrics and gynecology, 2017

Paediatric and Perinatal Epidemiology, 2013

American Journal of Perinatology Reports, 2013

Pediatric and Developmental Pathology, 2002

Pediatric and Developmental Pathology, 1998

Obstetrics & Gynecology, 2009

Obstetrics & Gynecology, 2014

New England Journal of Medicine, 2012

The Journal of Pediatrics, 2003

Paediatric and perinatal epidemiology, 2011

American Journal of Perinatology, 2011

American Journal of Obstetrics and Gynecology, 2014

PLoS Medicine, 2014

Pathology of the Placenta, 2018