Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis.

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease.

Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

Gestational hyperglycemia reprograms cardiac gene expression in rat offspring.

BackgroundRat fetuses with maternal pregestational hyperglycemia develop cardiac dysfunction, and their cardiac gene expression differs from that of healthy control fetuses near term. We hypothesized that cardiac gene expression and morphologic abnormalities of rat fetuses with maternal pregestational hyperglycemia become normal after birth.MethodsNine rats were preconceptually injected with streptozotocin to induce maternal hyperglycemia and nine rats served as controls. The hyperglycemia group comprised 82 mice and the control group 74 offspring fed by euglycemic dams. Hearts of the offspring were collected on postnatal days 0, 7, and 14, and processed for histologic and gene expression analyses.ResultsOn day 0, heart weight was increased, and expression of cardiac genes involved in contractility, growth, and metabolism was decreased in the hyperglycemia group. On day 7, although cardiomyocyte apoptosis was enhanced, most of the changes in gene expression had normalized in the hyperglycemia group. By day 14, the expression of genes important for myocardial growth, function, and metabolism was again abnormal in the hyperglycemia group.ConclusionMost cardiac gene expression abnormalities become transiently normal during the first week of life of offspring to hyperglycemic rats. However, by day 14, cardiac expressions of genes involved in growth, function, and metabolism are again abnormal in relation to control offspring.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients.

BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET.

BACKGROUND: The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). METHODS: [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome. RESULTS: None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014). CONCLUSIONS: A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.

Simultaneous p53 and p16 Immunostaining for Molecular Subclassification of Head and Neck Squamous Cell Carcinomas.

PURPOSE: Our aim was to assess the ability of simultaneous immunohistochemical staining (IHC) for p16 and p53 to accurately subclassify head and neck squamous cell carcinomas (HNSCC) as HPV-associated (HPV-A) versus HPV-independent (HPV-I) and compare p53 IHC staining patterns to TP53 mutation status, p16 IHC positivity and HPV status. METHODS: We stained 31 HNSCCs for p53 and p16, and performed next-generation sequencing (FoundationOne©CDx) on all cases and HPV in-situ hybridization (ISH) when sufficient tissue was available (n = 23). p53 IHC staining patterns were assessed as wildtype (wt) or abnormal (abn) patterns i.e. overexpression, null or cytoplasmic staining. RESULTS: In a majority of cases (28/31) interpretation of p16 and p53 IHC was straightforward; 10 were considered HPV-A (p16+/p53wt) and 18 cases were HPV-I (p16-/p53abn). In the remaining three tumours the unusual immunophenotype was resolved by molecular testing, specifically (i) subclonal p16 staining and wild type p53 staining in a tumour positive for HPV and with no TP53 mutation (HPV-A), (ii) negative p16 and wild type p53 staining with a TP53 mutation and negative for HPV (HPV-I), and (iii) equivocally increased p16 staining with mutant pattern p53 expression, negative HPV ISH and with a TP53 mutation (HPV-I). CONCLUSION: Performing p16 and p53 IHC staining simultaneously allows classification of most HNSCC as HPV-A (p16 +, p53 wild type (especially basal sparing or null-like HPV associated staining patterns, which were completely specific for HPV-A SCC) or HPV-I (p16 -, p53 mutant pattern expression), with the potential for limiting additional molecular HPV or mutational testing to selected cases only.

Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation.

Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non-transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype.

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma: Association with Metabolic Tumor Burden Determined with FDG-PET/CT.

BACKGROUND: The detection of circulating tumor DNA (ctDNA) with next-generation sequencing (NGS) in venous blood is a promising tool for the genomic profiling of head and neck squamous cell carcinoma (HNSCC). The association between ctDNA findings and metabolic tumor burden detected with FDG-PET/CT imaging is of particular interest for developing prognostic and predictive algorithms in HNSCC. METHODS: Twenty-six prospectively enrolled HNSCC patients were eligible for further analysis. All patients underwent tumor tissue and venous liquid biopsy sampling and FDG-PET/CT before definitive oncologic treatment. An NGS-based commercial panel was used for a genomic analysis of the samples. RESULTS: Maximum variant allele frequency (VAF) in blood correlated positively with whole-body (WB) metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (r = 0.510, p = 0.008 and r = 0.584, p = 0.002, respectively). A positive liquid biopsy was associated with high WB-TLG using VAF ≥ 1.00% or ≥5.00% as a cut-off value (p = 0.006 or p = 0.003, respectively). Additionally, ctDNA detection was associated with WB-TLG when only concordant variants detected in both ctDNA and tissue samples were considered. CONCLUSIONS: A high metabolic tumor burden based on FDG imaging is associated with a positive liquid biopsy and high maximum VAF. Our findings suggest a complementary role of metabolic and genomic signatures in the pre-treatment evaluation of HNSCC.

Functional brown adipose tissue in healthy adults.

Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy specimens of this tissue from the first three consecutive subjects and documented messenger RNA (mRNA) and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis.

BACKGROUND: Medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumours (PNETs) are the most common highly aggressive paediatric brain tumours. In spite of extensive research on these tumours, there are only few known biomarkers or therapeutic target proteins, and the prognosis of patients with these tumours remains poor. Our aim was to investigate whether carbonic anhydrases (CAs), enzymes commonly overexpressed in various tumours including glioblastomas and oligodendrogliomas, are present in MBs and PNETs, and whether their expression can be correlated with patient prognosis. METHODS: We determined the expression of the tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a series of MB/PNET specimens (n = 39) using immunohistochemistry. RESULTS: Endothelial CA II, cytoplasmic CA II, CA IX and CA XII were expressed in 49%, 73%, 23% and 11% of the tumours, respectively. CA II was detected in the neovessel endothelium and the tumour cell cytoplasm. CA IX was mainly expressed in the tumour cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumours. Importantly, CA IX expression predicted poor prognosis in both univariate (p = 0.041) and multivariate analyses (p = 0.016). CONCLUSIONS: We suggest that CA IX should be considered a potential prognostic and therapeutic target in MBs and PNETs.

Environmental services provided from riparian forests in the Nordic countries.

Riparian forests (RF) growing along streams, rivers and lakes comprise more than 2% of the forest area in the Nordic countries (considering a 10 m wide zone from the water body). They have special ecological functions in the landscape. They receive water and nutrients from the upslope areas, are important habitats for biodiversity, have large soil carbon stores, but may emit more greenhouse gases (GHG) than the uplands. In this article, we present a review of the environmental services related to water protection, terrestrial biodiversity, carbon storage and greenhouse gas dynamics provided by RF in the Nordic countries. We discuss the benefits and trade-offs when leaving the RF as a buffer against the impacts from upland forest management, in particular the impacts of clear cutting. Forest buffers are effective in protecting water quality and aquatic life, and have positive effects on terrestrial biodiversity, particularly when broader than 40 m, whereas the effect on the greenhouse gas exchange is unclear.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Differential expression of decorin by human malignant and benign vascular tumors.

An increasing amount of evidence indicates that a small extracellular chondroitin/dermatan sulfate proteoglycan, decorin, is indirectly involved in angiogenesis. Given that angiogenesis is a sine qua non for tumor growth and progression, we attempted to examine whether human malignant vascular tumors differ from human benign vascular tumors in terms of their decorin expression and synthesis. CD31 immunostaining demonstrated that the human malignant vascular tumors Kaposi's sarcoma and angiosarcoma were filled with capillary-like structures, whereas in benign cavernous and capillary hemangiomas, blood vessels were not as abundantly present. By utilizing in situ hybridization and immunocytochemical assays for decorin, we showed that there was no detectable decorin mRNA expression or immunoreactivity within the tumor mass in the Kaposi's sarcoma or angiosarcoma group. Instead, decorin was expressed in the connective tissue stroma lining the sarcoma tissue. In contrast to sarcomas, in hemangiomas, decorin mRNA expression and immunoreactivity were observed also within the tumor mass, particularly in the connective tissue stroma surrounding the clusters of intratumoral blood vessels. Finally, distribution of type I collagen was found to be similar to that of decorin in these tumor tissues. Our findings can be explained with different states of angiogenesis in dissimilar growths. In sarcomas, angiogenesis is extremely powerful, whereas in hemangiomas, angiogenesis has ceased. Thus, decorin is likely to possess a suppressive effect on human tumor angiogenesis in vivo, as previously described by studies using different experimental models. Decorin certainly provides a usable biomarker for distinguishing between benign and malignant vascular tumors in patients.

A familial CHARGE syndrome with a CHD7 nonsense mutation and new clinical features.

The autosomal dominant CHARGE syndrome (MIM musical sharp214800) is caused by mutations in the CHD7 gene. It is usually sporadic but a few cases with gonadal mosaicism and familial inheritance have been reported. We describe a familial CHARGE syndrome in a two-generation Finnish family with a nonsense mutation in the CHD7 gene. Detailed clinical examination of the affected family members was performed, and mutations in the CHD7 gene were analysed with direct sequencing and multiplex ligation-dependent probe amplification. A nonsense mutation, p.Q1599X, was detected in exon 21 of the CHD7 gene in three affected family members. The father was only mildly affected, whereas his son had a very severe manifestation of the syndrome, causing death at the age of 3 months. The second pregnancy was prematurely terminated in the 23rd week because of cardiac anomalies detected in the ultrasound scan. The father's brother also had mild symptoms, but no mutation was detected in him. In this report, the variability of clinical symptoms within families and the clinical importance of mildly affected patients with the CHARGE syndrome are underlined with implications for molecular genetic diagnostics of the syndrome. Features not described in the CHARGE syndrome before are also presented.

Increased Liver Fatty Acid Uptake Is Partly Reversed and Liver Fat Content Normalized After Bariatric Surgery.

OBJECTIVE: Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery. RESEARCH DESIGN AND METHODS: Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects. RESULTS: The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased. CONCLUSIONS: The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively.

Novel COL1A1 Mutation c.3290G>T Associated With Severe Form of Osteogenesis Imperfecta in a Fetus.

Osteogenesis imperfecta is a genetically and clinically heterogenous group of skeletal dysplasias characterized by bone fragility. Its severity ranges from nearly asymptomatic individuals to perinatal lethality. The majority of cases are caused by mutations in either the COL1A1 or the COL1A2 gene coding for alpha 1 and alpha 2 chains of collagen type 1, respectively, and a large number of pathogenic variants of these genes has been identified. We describe a novel COL1A1 mutation associated with prenatally diagnosed severe form of osteogenesis imperfecta.

Causes of Stillbirth in Turku, Finland, 2001-2011.

The objective of the study was to examine the causes of stillbirth in the district of Southwest Finland and to assess the importance of postmortem examination and the selection of a suitable classification system for classifying stillbirths. This study is a cohort study where the fetal autopsies were performed in the Department of Pathology at Turku University Hospital, Finland, 2001-2011. Stillbirths from singleton pregnancies at the gestational age of ≥ 24 + 0 weeks (if unknown, gestational weight ≥ 500 g) (n = 98) were selected. In addition, stillbirths from multiple gestations (n = 6) were also analyzed. The causes of stillbirths were classified according to the Relevant Condition at Death classification system. Maternal risk factors and the role of fetal gestational age and weight for the causes of stillbirth were assessed. The most common causes of singleton stillbirth were lethal congenital anomalies, placental insufficiencies, and constricting loops and knots of the umbilical cord. The cause of singleton stillbirth could be determined for 78% of the cases, leaving 22% unclassified. There were no significant differences in the causes of stillbirth by gestational age or weight. Smoking may increase the incidence of placental abruption ( P < 0.01). The most common causes of stillbirth in Turku, Finland, are consistent with findings from other high-income countries. With careful postmortem examination and ancillary studies, it is possible to find the cause of stillbirth for most of the cases. Even if the stillbirth is left unexplained, many other harmful conditions can be excluded thus benefiting both the parents and the health care unit.

Methanogen communities along a primary succession transect of mire ecosystems.

Peat accumulating mires are important sources of the greenhouse gas methane. Methane emissions and methanogenic Archaea communities have been shown to differ between fens and bogs, implying that mire succession includes an ecological succession in methanogen communities. We investigated methane production and the methanogen communities along a chronosequence of mires (ca. 100-2,500 years), which consisted of five sites (1-5) located on the land-uplift coast of the Gulf of Bothnia. Methane production was measured in a laboratory incubation experiment. Methanogen communities were determined by amplification of a methyl coenzyme M-reductase (mcr) gene marker and analyzed by terminal-restriction fragment length polymorphism. The terminal-restriction fragment length polymorphism fingerprinting resulted in 15 terminal restriction fragments. The ordination configuration of the terminal restriction fragments data, using nonmetric multidimensional scaling, showed a clear gradient in the methanogen community structure along the mire chronosequence. In addition, fingerprint patterns of samples from the water table level and 40 cm below differed from one another in the bog site (site 5). Methane production was negligible in the three youngest fen sites (sites 1-3) and showed the highest rates in the oligotrophic fen site (site 4). Successful PCR amplification using mcr gene primers revealed the presence of a methanogen community in all five sites along the study transect.

Placental structural abnormalities have detrimental hemodynamic consequences in a rat model of maternal hyperglycemia.

INTRODUCTION: Human type 1 diabetic pregnancy is associated with placental structural and hemodynamic abnormalities. We hypothesized that in rat fetuses of hyperglycemic dams, placental and fetal blood flow velocity waveforms demonstrate compromised hemodynamics when compared to control fetuses, and these hemodynamic parameters correlate with placental structural abnormalities at near term gestation. METHODS: Streptozotocin-induced maternal hyperglycemia group comprised 10 dams with 107 fetuses and the control group 20 dams with 219 fetuses. Doppler-ultrasonographic examinations were performed at gestational days 13-14, 16-17, and 19-21. After the last examination, placentas were collected for morphologic, gene expression, and cytokine analysis. RESULTS: Umbilical artery (UA), descending aorta (DAO), and ductus venosus (DV) pulsatility indices (PI) were significantly higher at each study point in maternal hyperglycemia compared to controls. Placental size, glycogen storages, venous thrombosis formation, and fluid accumulation were increased in maternal hyperglycemia. Epidermal growth factor receptor (Edgfrb), platelet derived growth factor receptor beta polypeptide (Pdgfrb), and tumor necrosis factor receptor superfamily, member 12α (Tnfrsf12α) expressions were decreased. Interleukin (IL) -2 and -4 concentrations were decreased, and IL-1beta levels were increased in maternal hyperglycemia. UA PIs correlated positively with DV PIV, DAO PI, fluid accumulation, and glycogen storages. UA PIs correlated negatively with IL-4, Edgfrb, and Pdgfrb. DISCUSSION: In maternal hyperglycemia, placental and fetal hemodynamics were compromised during the last trimester of pregnancy compared to normoglycemic pregnancies. Placental structural, metabolic, and growth related gene expression, and inflammatory marker abnormalities were associated with hemodynamic compromise.

Angiotensin II receptor inhibition prevents pneumocyte apoptosis in surfactant-depleted rat lungs.

Pneumocyte apoptosis is implicated in the pathophysiology of acute inflammatory lung injuries in newborns and adults. Pulmonary angiotensin (ANG) II contributes to lung epithelial apoptosis in vitro, but its role in acute lung injury in vivo is unclear. We therefore studied the effects of ANG II receptor action on the pulmonary inflammatory and apoptotic changes in surfactant-depleted lungs in rats. Lung injury was induced by repeated lung lavage with saline, and the rats were then ventilated with 60% oxygen for 1, 3, or 5 hr. Separate groups of rats were pretreated with a nonspecific ANG II receptor inhibitor saralasin, the specific ANG II type 1 receptor antagonist losartan, or ANG II type 2 receptor inhibitor PD123319, and were similarly studied. Lungs were studied histologically for tissue injury, and with terminal deoxynucleodityl transferase-mediated dUTP nick end-labeling (TUNEL) and cleaved caspase 3 antibody staining, and by electron microscopy for apoptotic cell death. Surfactant-depleted lungs showed an increased number of TUNEL-positive epithelial cells throughout the study, and intrapulmonary leukocyte migration and histological tissue injury scores were similarly elevated, compared to controls, from 1-5 hr of ventilation. Pretreatment with saralasin or losartan significantly prevented the increase of TUNEL positivity in pneumocytes, but had no effect on the amount of neutrophil influx or total injury score in lavaged lungs. In contrast, administration of PD123319 did not affect the number of TUNEL-positive epithelial cells or histological injury . The results suggest that increased epithelial apoptosis in surfactant-deficient lungs is mediated by ANG II receptor (specifically, subtype 1) action.