Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19 439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.

Background In March 2020, COVID-19 was declared to be a pandemic. While data suggests that COVID-19 is not associated with significant adverse health outcomes for pregnant women and newborns, the psychological impact on pregnant women is likely to be high. Aim The aim was to explore the psychological impact of the COVID-19 pandemic on Italian pregnant women, especially regarding concerns and birth expectations. Methods A cross-sectional online survey of pregnant women in Italy was conducted. Responses were analysed for all women and segregated into two groups depending on previous experience of pregnancy loss. Analysis of open text responses examined expectations and concerns before and after the onset of the pandemic. Findings Two hundred pregnant women responded to the first wave of the survey. Most (n = 157, 78.5%) had other children and 100 (50.0%) had a previous history of perinatal loss. ‘Joy’ was the most prevalent emotion expressed before COVID-19 (126, 63.0% before vs 34, 17.0% after; p < 0.05); fear was the most prevalent after (15, 7.5% before vs 98, 49.0% after; p < 0.05). Positive constructs were prevalent before COVID-19, while negative ones were dominant after (p < 0.05). Across the country, women were concerned about COVID-19 and a history of psychological disorders was significantly associated with higher concerns (p < 0.05). A previous pregnancy loss did not influence women’s concerns. Conclusions Women’s expectations and concerns regarding childbirth changed significantly as a result of the COVID-19 pandemic in Italy. Women with a history of psychological disorders need particular attention as they seem to experience higher levels of concern.

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We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs) by analyzing COX-2 expression and prostaglandin E2 (PGE2) production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF) mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P<.0001). Specimens from patients with lymph node metastasis exhibited higher COX-2 protein expression (P=.0074), PGE2 levels (P=.0011) and microvessel density (P<.0001) than specimens from patients without metastasis. A significant correlation between COX-2 and tumor vascularization (r(s)=0.450, P=.007) as well as between COX-2 and microvessel density with VEGF expression in tumor tissues was found (r(s)=0.450, P=.007; r(s)=0.620, P=.0001, respectively). The induction of COX-2 mRNA and PGE2 synthesis by EGF and Escherichia coli lipopolysaccharide (LPS) in A-431 and SCC-9 cell lines, resulted in an increase in VEGF mRNA and protein production. Indomethacin and celecoxib reversed the EGF- and LPS-dependent COX-2, VEGF, and PGE2 increases. This study suggests a central role of COX-2 pathway in HNC angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors may be useful in HNC treatment.

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To obtain further information on time course and mechanisms of cell death after poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, we used HeLa cells exposed for 1 h to the DNA alkylating agent N-methyl-N-nitro-N-nitrosoguanidine. This treatment activated PARP-1 and caused a rapid drop of cellular NAD(H) and ATP contents, culminating 8 -12 h later in cell death. PARP-1 antagonists fully prevented nucleotide depletion and death. Interestingly, in the early 60 min after challenge with N-methyl-N-nitro-N-nitrosoguanidine, mitochondrial membrane potential and superoxide production significantly increased, whereas cellular ADP contents decreased. Again, these events were prevented by PARP-1 inhibitors, suggesting that PARP-1 hyperactivity leads to mitochondrial state 4 respiration. Mitochondrial membrane potential collapsed at later time points (3 h), when mitochondria released apoptosis-inducing factor and cytochrome c. Using immunocytochemistry and targeted luciferase transfection, we found that, despite an exclusive localization of PARP-1 and poly(ADP-ribose) in the nucleus, ATP levels first decreased in mitochondria and then in the cytoplasm of cells undergoing PARP-1 activation. PARP-1 inhibitors rescued ATP (but not NAD(H) levels) in cells undergoing hyper-poly(ADP-ribosyl)ation. Glycolysis played a central role in the energy recovery, whereas mitochondria consumed ATP in the early recovery phase and produced ATP in the late phase after PARP-1 inhibition, further indicating that nuclear poly(ADP-ribosyl)ation rapidly modulates mitochondrial functioning. Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death.The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) 1 converts ␤-nicotinamide-adenine dinucleotide (NAD) into polymers of poly(ADP-ribose) (PAR), which participate in regulating nuclear homeostasis (1). However, once hyperactivated by genotoxic stress, PARP-1 causes NAD and ATP depletion, eventually leading to irreversible cellular energy failure and necrotic death (2-6). The pathophysiological significance of PARP-1 hyperactivation is well exemplified by the remarkable therapeutic efficacy of PARP-1 inhibitors in experimental models of disorders characterized by DNA damage, such as ischemia, diabetes, shock, inflammation, and cancer (7). Recently, several studies have broadened the role of poly(ADP-ribosyl)-ation in cell killing, showing that PARP-1 activation also occurs during apoptosis, and inhibition of PAR formation impairs activation of the apoptotic machinery (for reviews see Refs. 8 and 9). In particular, it has been reported that PARP-1 prompts a cascade of events leading to PAR-dependent mitochondrial dysfunction and rapid release of apoptosis-inducing factor (AIF) (10 -12).Despite their pathogenetic relevance, however, molecular mechanisms underlying energetic derangement during PARP-1 hyperactivation still wait to be clarified. For instance, whether nuclear or mitochondrial PARP-1 hyperactivity triggers mi...

To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.

In animal models of inflammation, the pregnancy hormone relaxin was shown to reduce the recruitment of leukocytes, especially neutrophils, in inflamed tissues. The current study was designed to clarify whether relaxin could inhibit activation of isolated human neutrophils and, if so, whether the nitric oxide (NO) biosynthetic pathway was involved, as occurs in other relaxin targets. Human neutrophils were preincubated with 1, 10, and 100 nmol/liter porcine relaxin for 1 h before activation with N-formyl-Met-Leu-Phe (10 micromol/liter) or phorbol-12-myristate-13-acetate (0.1 micromol/liter). In selected experiments, the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 100 micromol/liter) was added to the samples 30 min before relaxin. In other experiments, chemically inactivated relaxin (10 nmol/liter) was substituted for authentic relaxin. Untreated, nonactivated neutrophils were the controls. Relaxin reduced significantly and in a concentration-dependent fashion the expression of the surface activation marker CD11b, as well as the generation of superoxide anion, the rise of intracellular Ca(2+), the release of cytoplasmic granules, and the chemotactic migration. These effects of relaxin were blunted by N(G)-monomethyl-L-arginine and could not be reproduced by inactivated relaxin. Relaxin also increased neutrophil inducible NO synthase expression and NO generation. This study provides evidence that relaxin inhibits the activation of human neutrophils stimulated by different proinflammatory agents. This novel property of relaxin could be of relevance in toning down maternal neutrophil activation during pregnancy, thereby counteracting the occurrence of pregnancy-related disorders such as preeclampsia, which is regarded as an excess maternal inflammatory response to pregnancy.