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Objective(s): This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients., Study Design: Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed., Results: A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded., Conclusion: Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women., (© 2021 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2'-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC 50 : 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC 50 HDAC3 =0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC 50 values at single-digit to sub-micromolar level., (© 2020 Wiley-VCH GmbH.)

The molecular mechanisms of reduced frataxin ( FXN ) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN -GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Vilema-Enríquez et al.)

Background: Smaller needles gauge (G) may reduce pain and improve vein access in difficult venous access (DVA). Aims were to compare the performances of two Beckton-Dickinson (BD) Vacutainer® Blood Collection Sets in a pediatric setting: UltraTouch™ Push Button (UT-PBBCS) and Safety-Lok™ (SLBCS)., Materials and Methods: Questionnaires were used to record venipuncture features, patient pain perception and phlebotomist difficulty score. Specimen quality was evaluated by hemolysis index (HI) on Roche Cobas® 6000., Results: SLBCS (21/23G) or UT-PBBCS (23/25G) were used in 211 (50.2%) and 209 (49.8%) subjects. Pain was associated with age (p < 0.0001) and was lower in UT-PBBCS (p = 0.0339). Difficulty was significantly associated with age (p = 0.002), not with needle gauge (p = 0.461) and it was 0.42 points lower in UT-PBBCS. HI was not associated with blood collection set (p = 0.385)., Conclusions: UT-PBBCS globally performed better than SLBCS and could enhance phlebotomy and patient comfort, without affecting sample quality in pediatric patients with DVA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: DNA methyltransferases (DNMTs) are epigenetic enzymes involved in embryonic development, cell differentiation, epithelial to mesenchymal transition, and control of gene expression, whose overexpression or enhanced catalytic activity has been widely reported in cancer initiation and progression. To date, two DNMT inhibitors (DNMTi), 5-azacytidine (5-AZA) and 5-aza-2'-deoxycytidine (DAC), are approved for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Nevertheless, they are chemically instable and quite toxic for healthy cells; thus, the discovery of novel DNMTi is urgent., Results: Here, we report the identification of a new quinoline-based molecule, MC3353, as a non-nucleoside inhibitor and downregulator of DNMT. This compound was able, in promoter demethylating assays, to induce enhanced green fluorescence protein (EGFP) gene expression in HCT116 cells and transcription in a cytomegalovirus (CMV) promoter-driven luciferase reporter system in KG-1 cells. Moreover, MC3353 displayed a strong antiproliferative activity when tested on HCT116 colon cancer cells after 48 h of treatment at 0.5 μM. At higher doses, this compound provided a cytotoxic effect in double DNMT knockout HCT116 cells. MC3353 was also screened on a different panel of cancer cells (KG-1 and U-937 acute myeloid leukemia, RAJI Burkitt's lymphoma, PC-3 prostate cancer, and MDA-MB-231 breast cancer), where it arrested cell proliferation and reduced viability after 48 h of treatment with IC 50 values ranging from 0.3 to 0.9 μM. Compared to healthy cell models, MC3353 induced apoptosis (e.g., U-937 and KG-1 cells) or necrosis (e.g., RAJI cells) at lower concentrations. Importantly, together with the main DNMT3A enzyme inhibition, MC3353 was also able to downregulate the DNMT3A protein level in selected HCT116 and PC-3 cell lines. Additionally, this compound provided impairment of the epithelial-to-mesenchymal transition (EMT) by inducing E-cadherin while reducing matrix metalloproteinase (MMP2) mRNA and protein levels in PC-3 and HCT116 cells. Last, tested on a panel of primary osteosarcoma cell lines, MC3353 markedly inhibited cell growth with low single-digit micromolar IC 50 ranging from 1.1 to 2.4 μM. Interestingly, in Saos-2 osteosarcoma cells, MC3353 induced both expression of genes and mineralized the matrix as evidence of osteosarcoma to osteoblast differentiation., Conclusions: The present work describes MC3353 as a novel DNMTi displaying a stronger in cell demethylating ability than both 5-AZA and DAC, providing re-activation of the silenced ubiquitin C-terminal hydrolase L1 (UCHL1) gene. MC3353 displayed dose- and time-dependent antiproliferative activity in several cancer cell types, inducing cell death and affecting EMT through E-cadherin and MMP2 modulation. In addition, this compound proved efficacy even in primary osteosarcoma cell models, through the modulation of genes involved in osteoblast differentiation.

Myelopoiesis was evaluated in 66 pediatric patients with chronic neutropenia who were positive for anti-neutrophil antibodies (median age at diagnosis: 11 months, median neutrophil count at diagnosis: 419/μl). Other causes of neutropenia were excluded. Bone marrow morphology, clonogenic tests and/or the peripheral blood CD 34+ cell count, and apoptotic rate were evaluated in 61 patients with neutropenia lasting > 12 months or severe infections. The peripheral blood CD 34+ cell count and apoptotic rate were evaluated in five patients with shorter neutropenia. The median follow-up time was 29 months (range 7-180 months). Forty-seven patients (71.2%) had a spontaneous recovery after 7-180 months (median 29 months). The group of patients younger than 24 months at diagnosis (n = 50) had a higher probability of recovery (40/50 vs. 7/16 χ2 p<0.01) with a shorter period of neutropenia (median 26 versus 47 months, Kaplan-Meier analysis p = 0.001). The colony-forming units-granulocyte-macrophage (CFU-GM) were significantly decreased in 26/35 patients (74%) evaluated for clonogenic tests. All patients with normal CFU-GM recovered (9/9 patients); whereas, neutropenia persisted in 12/26 patients with reduced CFU-GM (46%, Pearson χ2 p = 0.02). In 36/55 (65%) patients evaluated by flow cytometry we observed reduced circulating CD34+ cells compared with controls of the same age. An increase in the circulating CD34+ cell apoptotic rate was observed in 28/55 patients (51%). Infections requiring hospitalization were observed in 9/18 (50%; Pearson χ2, p = 0.03) patients with both decreased circulating CD34+ cells and increased CD34+ apoptotic rates. In the group aged < 24 months, we observed a significant correlation between the persistence of neutropenia and decreased circulating CD34+ cells (Pearson χ2 p = 0.008). In conclusion, reduced CFU-GM and circulating hematopoietic progenitors were observed in a subgroup of children with chronic neutropenia who were positive for anti-neutrophil antibodies and had a higher incidence of severe infections and delayed spontaneous remission., Competing Interests: The authors have declared that no competing interests exist.

Epigenetic pathways play a pivotal role in the development and function of the immune system. Over the last decade, a growing body of studies has been published out seeking to explain a correlation between epigenetic modifications and the development of autoimmune disorders. Epigenetic changes, such as DNA methylation, histone modifications, and noncoding RNAs, are involved in the pathogenesis of autoimmune diseases mainly by regulating gene expression. This paper reviews the importance of epigenetic alterations during the development of the most prevalent human autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Sjogren's syndrome (SS), autoimmune thyroid diseases (AITD), and type 1 diabetes (T1D), aiming to provide new insights in the pathogenesis of autoimmune diseases and the possibility to develop novel therapeutic approaches targeting the epigenome.

In aggressive tumors, alkylglyceronephosphate synthase (AGPS) controls cellular ether phospholipid utilization and metabolism to promote cancer cell proliferation and motility. SAR studies on the first-in-class AGPS inhibitor 1, discovered by our group, led to the 2,6-difluoro analog 2i which showed higher binding affinity than 1in vitro. In 231MFP cancer cells, 2i reduced ether lipids levels and cell migration rate. When tested in PC-3 and MDA-MB-231 cancer cells, 2i specifically impaired epithelial to mesenchymal transition (EMT) by modulating E-cadherin, Snail and MMP2 expression levels. Moreover, the combination of siRNAs against AGPS and 2i provided no additive effect, confirming that the modulation of 2i on EMT specifically relies on AGPS inhibition. Finally, this compound also affected cancer cell proliferation especially in MDA-MB-231 cells expressing higher AGPS level, whereas it provided negligible effects on MeT5A, a non-tumorigenic cell line, thus showing cancer specificity., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Despite the recent reductions in the global burden of malaria, this disease remains a devastating cause of death in tropical and subtropical regions. As there is no broadly effective vaccine for malaria, prevention and treatment still rely on chemotherapy. Unfortunately, emerging resistance to the gold standard artemisinin combination therapies means that new drugs with novel modes of action are urgently needed. In this context, Plasmodium histone modifying enzymes have emerged as potential drug targets, prompting us to develop and optimize compounds directed against such epigenetic targets. A panel of 51 compounds designed to target different epigenetic enzymes were screened for activity against Plasmodium falciparum parasites. Based on in vitro activity against drug susceptible and drug-resistant P. falciparum lines, selectivity index criterion and favorable pharmacokinetic properties, four compounds, one HDAC inhibitor (1) and three DNMT inhibitors (37, 43 and 45), were selected for preclinical studies in a mouse model of malaria. In vivo data showed that 37, 43 and 45 exhibited oral efficacy in the mouse model of Plasmodium berghei infection. These compounds represent promising starting points for the development of novel antimalarial drugs., (Crown Copyright © 2018. Published by Elsevier Masson SAS. All rights reserved.)

The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G 1 or G 2 -M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881-92. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine. Compound 4 emerged as the most promising of the synthesized series, showing good inhibitory activity towards HDAC1 and LSD1 either in vitro and in cell-based assay (Ki = 42.52 ± 8.94 nM and IC 50  = 3.85 μM, respectively). Furthermore, at 70.0 µM compound 4 induced a more pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of dead cells) in MCF7 cancer cell line., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Strategies to prevent anaemia in preterm infants include drawing fewer blood samples, the use of recombinant human erythropoietin and iron supplementation. Although iron sulfate is the most commonly used pharmaceutical formulation for iron supplementation, there are few studies comparing different iron salts in infants., Objective: This is a study of retrospective data comparison of two groups of preterm infants receiving erythropoietin to evaluate the efficacy of iron bisglycinate chelate to iron sulfate., Subjects and Methods: Three-hundred infants of gestational age ≤32 weeks were enrolled: 225 were supplemented with iron sulfate (3 mg/kg/day) and 75 were supplemented with iron bisglycinate chelate (0.75 mg/kg/day). The effect on erythropoiesis was assessed with a general linear model that estimates the response variables (values for Haemoglobin, Haematocrit, absolute values and percentage Reticulocytes, Reticulocyte Haemoglobin content) based on treatment, time, birth weight, and gestational age., Results: Supplementation with iron bisglycinate chelate at a dose of 0.75 mg/kg/day demonstrated an efficacy comparable to iron sulfate at a dose of 3 mg/kg/day in both populations of preterm infants. The two cohorts had similar erythropoietic response, without significant differences., Conclusions: The higher bioavailability of iron bisglycinate chelate resulted in a lower load of elemental iron, a quarter of the dose, and achieved equivalent efficacy compared to iron sulfate. Iron bisglycinate chelate may appear to be an alternative to iron sulfate in the prevention and treatment of preterm newborn anaemia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Immune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system. To overcome some major limitations and ensure safety in patients, recent strategies have shown that combining epigenetic modulators, such as inhibitors of histone deacetylases (HDACi) or DNA methyltransferases (DNMTi), with immunotherapeutics can be useful. Preclinical data generated using mouse models strongly support the feasibility and effectiveness of the proposed approaches. Indeed, co-treatment with pan- or class I-selective HDACi or DNMTi improved beneficial outcomes in both in vitro and in vivo studies. Based on the evidence of a pivotal role for HDACi and DNMTi in modulating various components belonging to the immune system, recent clinical trials have shown that both HDACi and DNMTi strongly augmented response to anti-PD-1 immunotherapy in different tumour types. This review describes the current strategies to increase immunotherapy responses, the effects of HDACi and DNMTi on immune modulation, and the advantages of combinatorial therapy over single-drug treatment.

This study examined the impact of U.S. chain restaurant food consumption in China and South Korea from an ecological perspective. Specifically, it explored the relationships among several environmental and individual variables that have been found to affect obesity/weight management in previous research, including the prevalence/popularity of U.S. chain restaurants in these countries, frequency of U.S. chain restaurant food consumption, self-efficacy in weight management, willingness to communicate about weight/diet, self-perceptions of weight/obesity stigma, body mass index (BMI), and depression. The results indicated that willingness to communicate about weight/diet predicted increased self-efficacy in weight management. Higher BMI scores were found to predict increased weight/obesity stigma, and increased frequency of U.S. restaurant food consumption, weight/obesity stigma, and reduced self-efficacy in weight management were found to predict increased levels of depression. The theoretical and practical implications of the findings are discussed, along with limitations and directions for future research.

We report data regarding kinetic of response to oral iron in 34 iron deficiency anemia children. Twenty-four/34 patients (70.5%) reached reference value of hemoglobin (Hb) concentration for age and sex at day + 30 from the beginning of treatment (complete early responders (CERs)), and 4/34 (12%) reached an Hb concentration at least 50% higher than the original (partial early responders (PERs)). CHr at T1 (within 7 days from the beginning of treatment) was significantly different in the different groups (22.95 in CERs versus 18.41 in other patients; p = 0.001; 22.42 in early responders versus 18.07 in NERs; p = 0.001). Relative increase of CHr from T0 to T1 resulted significantly higher in CERs than in other patients (0.21 versus 0.11, p = 0.042) and in early responders than in NERs (0.22 versus 0.004, p = 0.006). Multivariate logistic models revealed a higher probability of being a complete early responder due to relative increase of ARC from T0 to T1 [OR (95% CI) = 44.95 (1.54-1311.98)] and to CHr at T1 [OR (95% CI) =3.18 (1.24-8.17)]. Our preliminary data confirm CHr as early and accurate predictor of hematological response to oral iron.

The aim of the present study was to determine the effects of exclusive oral iron supplementation (iron sulphate 2 mg/kg/die) in asymptomatic children with severe iron-deficiency anemia [median hemoglobin (Hb) level before treatment 6.3 g/dL; range 4.5 to 7 g/dL] and to investigate the accuracy of Hb, reticulocyte hemoglobin content (CHr), and absolute reticulocyte count (ARC) as markers for monitoring early response to treatment. The increase in ARC and CHr was statistically significant at day +3. There was a significant association between suitable logarithmic functions of the percentage increase in CHr and ARC at day +3 and the fraction of required Hb increase compared with baseline to reach the mean reference value for age and sex at day +14. If these results are confirmed in a larger population, ARC and CHr could be considered affordable and widely available markers to detect early responders to oral iron therapy, and to switch unresponsive children to parenteral iron supplementation or transfusion.

In this case-report a case of severe fetal anemia of unknown origin is presented. Diagnosis of fetal anemia was made at 24 weeks of gestational age, when fetal ascites was identified. Doppler sonography of medium cerebral artery showed a high systolic speed velocity (ACM-PSV), of 65 cm/s (>1.55 MoM). This value predicts a severe fetal anemia. Funicolocentesis confirmed hyporegenerative anemia, low reticulocytosis and low erythroblastosis. A fetal transfusion was performed. At birth anemia was still present and the baby presented blueberry muffin and liver erythropoietic foci. The blueberry muffin morphology presents as non-blanching, blue-red macules or firm, dome-shaped papules (2-8 mm in diameter). The eruption is often generalized but favors the trunk, head, and neck. Infectious (Toxoplasmosis, Cytomegalovirus, Rubella, Herpes, Parvo, Coxackievirus, Ebstein Barr, Syphilis), hematologic (sferocytosis, alloimmunization, foeto-maternal transfusion), metabolic, neoplastic (congenital leukemia, neuroblastome, congenital rhabdomyosarcome) and systemic (histiocytosis, lupus) pathologies indicated until now as possible disease causes were excluded. In the first day of life the neonate received a RBC transfusion for anemia (Hb=5.1 g/dL; Hct 15,7% at birth), followed within 48-72 hours by rapid disappearance of the rash, that wasn't then histologically examined. During two weeks of hospitalization reticulocytes raised spontaneously from 0.8% to 3.17%. Until two years of age the auxologic and clinical course was regular and the child is now in good health conditions. Due to the absence of systematic disease and the complete regression, no exact diagnosis and prognosis could be established in this case.

The risk of Down's syndrome pregnancies can be estimated by quantitation of maternal serum markers, namely alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin (triple test). A prospective study of 2892 pregnant women (median age 33.5 years) is reported. The detection rate of Down's syndrome pregnancies was 80% (confidence intervals 45%-100%) when a risk of 1:380 or greater was considered "screen positive", the false positive rate was 13.3% (confidence intervals 12.0%-14.5%). The importance of the accurate assessment of gestational age and the time of blood sampling are emphasized. Our findings are compared with similar studies performed in other laboratories.

The effectiveness of maternal serum alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin in screening for Down's syndrome (DS) was evaluated on 840 women who underwent amniocentesis for fetal karyotype on account of their age. The risk of a DS pregnancy was established using the method of Wald et al. (1988b), which combines the age-specific risk with that indicated by the levels of the three serum markers. In women over 35, at cut-off risk levels of 1:250 and 1:380, the false-positive rate was 24 and 34 per cent, respectively. In all nine cases of DS, the estimated risk was higher than 1:250. The best screening strategy with the lowest false-positive rate was obtained by combining the three serum markers. The results suggest that this kind of screening can be proposed during genetic counselling for women under 35 and older women wishing to avoid the risk of miscarriage induced by amniocentesis.

To understand the structural basis of avian gas exchange better, we made a morphometric study of domestic and Canada goose lungs. The volume of glutaraldehyde-fixed domestic goose lungs (30 cm3/kg body weight) was similar to that determined from silicone casts of Canada goose lungs by Duncker (33 cm3/kg). To examine finer structures, we rapidly froze goose lungs under physiologic conditions, fixed tissue samples by a freeze substitution procedure and analyzed samples with stereological methods. From light micrographs we determined that about 55% of the lung is parabronchi in both species. Volume densities of air capillaries, blood capillaries and tissue and surface:volume ratios of these same structures were determined from electron micrographs. Our measurements agree with those from glutaraldehyde-fixed Canada goose lungs from other laboratories. Gas exchange surface area was largest in the good flier (Canada goose) but both birds had larger surface areas than comparably sized mammals. The harmonic mean blood-gas barrier thickness is smaller in both species of birds (0.3 microns) than in mammals. Thus, membrane diffusing capacities for gases should be larger in birds than in mammals. Pulmonary blood capillary transit time, as calculated from blood capillary volume and normal levels of cardiac output, are longer in birds than in mammals and should allow more time for blood-gas equilibrium. Pleats and folds were frequently observed in air and blood capillaries, suggesting that the avian lung may not be as rigid as was previously thought and that capillary volumes and surface areas may change under physiologic conditions.