Increased urinary albumin leakage is related to injuries of glomerular glycocalyx and podocytes, and associated with tubular dysfunction in preeclampsia.

OBJECTIVE: The pathogenesis of preeclampsia (PE) is known to be endothelial cell damage; however, the existence of dysfunction in glomerular endothelial glycocalyx, podocytes and tubules remains unclear. The glomerular endothelial glycocalyx, basement membrane, podocytes, and tubules are permeability barriers against albumin excretion. This study aimed to assess the relationship between urinary albumin leakage and injuries of the glomerular endothelial glycocalyx, podocytes, and tubules in patients with PE. METHODS: A total of 81 women with uncomplicated pregnancies (control, n = 22), PE (PE, n = 36), or gestational hypertension (GH) (GH, n = 23) were enrolled. We assessed urinary albumin and serum hyaluronan for glycocalyx injuries, podocalyxin for podocytes injuries, and urinary N-acetyl-ß-d-glucosaminidase (NAG) and liver-type fatty acid-binding protein (l-FABP) for renal tubular dysfunctions. RESULTS: The serum hyaluronan and the urinary podocalyxin levels were higher in the PE and GH groups. The urinary NAG and l-FABP levels were higher in the PE group. Urinary NAG and l-FABP levels positively correlated with urinary albumin excretion. CONCLUSIONS: Our findings suggest that increased urinary albumin leakage is related to injuries of the glycocalyx and podocytes, and associated with tubular dysfunction in pregnant women with PE. The clinical trial described in this paper was registered at the UMIN Clinical Trials Registry under registration number UMIN000047875. URL of registration: https://centre6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054437.

Amount of proteinuria as associated with severity classification of pregnant women with preeclampsia.

OBJECTIVE: This study aimed to verify whether the severity classification of preeclamptic women differed by the presence or absence of proteinuria exceeding 2.0 g/24 h. METHODS: In this retrospective cohort study, data were collected from women with singleton pregnancies who presented with preeclampsia and proteinuria at Aichi Medical University Hospital between April 1, 2008 and September 30, 2021. Participants were divided into two groups (high proteinuria and low proteinuria) based on whether or not their proteinuria exceeded 2.0 g/24 h. Between the two groups, severity of maternal was assessed using the American College of Obstetricians and Gynecologists (ACOG) severity classification (Severe Features) and perinatal and neonatal outcomes were compared. RESULTS: Relative to preeclamptic women with lower proteinuria group, those with higher proteinuria group delivered and were diagnosed with preeclampsia at an earlier gestational week. The latter group also exhibited higher rates of pleural effusion or ascites, preterm birth, and early preterm birth, in addition to lower birth weight and birth weight SD. Rates of admission to the NICU were also higher for neonates born to preeclamptic women in the higher proteinuria group. The percentage of women classified as 'severe' was higher in the higher proteinuria group relative to that in the lower proteinuria group. The percentage of those with severe hypertension and new-onset headache was higher in the higher proteinuria group compared to the lower proteinuria group. The optimal proteinuria cutoff value that distinguished between severe and non-severe maternal cases was determined to be 2.2 g/24 h. CONCLUSIONS: Severity classifications were more common among preeclamptic women with proteinuria exceeding 2.0 g/24 h, particularly with regard to the percentage of those with severe hypertension and new-onset headache.

Hypoalbuminemia is related to endothelial dysfunction resulting from oxidative stress in parturients with preeclampsia.

Serum albumin levels are inversely related with oxidative stress, but positively related with endothelial function, in pregnant women. However, it is unclear whether hypoalbuminemia in pregnant women with preeclampsia (PE) increases the production of oxygen-derived free radicals and impacts endothelial function. The present study aimed to assess the relationship between serum albumin, oxidative stress, and endothelial dysfunction in pregnant women with PE. A total of 75 women with control pregnancy (Control group, n = 30), PE (PE group, n = 24), or gestational hypertension (GH) (GH group, n = 21) were enrolled. We assessed serum albumin levels, diacron-reactive oxygen metabolites (d-ROMs) as an oxygen-derived free radical marker, and flow-mediated dilation (FMD) as a readout for vascular endothelial function during the gestational period and at one month after delivery. During the gestational period, FMD was lower, but d-ROM levels were higher, in the PE and GH groups compared with the Control group. Serum albumin levels were lower in the PE group compared with the Control and GH groups. d-ROM levels were inversely correlated with serum albumin levels (r = -0.54, p < 0.05) and FMD (r = -0.56, p < 0.05) in the PE group, and negatively correlated with FMD, but not serum albumin levels, in the GH group. Serum levels of d-ROMs and albumin, as well as FMD, were similar between groups after delivery. Our findings suggest that reduced serum albumin levels enhance the production of oxygen-derived free radicals, resulting in impaired maternal vascular endothelial function in parturients with PE.

Placental hypoplasia and maternal organic vascular disorder in pregnant women with gestational hypertension and preeclampsia.

Objective: This study aimed to investigate the etiology and pathology of preeclampsia (PE), a two-stage disorder involving uteroplacental dysfunction resulting from abnormal implantation and placentation, and gestational hypertension (GH), for which maternal organic vascular disorder is often an underlying factor.Methods: We assessed concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and antiangiogenic factor (sFlt-1), placental hypoxic changes, oxidative DNA damage, and maternal organic vascular disorders in 23 women with PE (PE group), 13 with GH (GH group), and 16 with uncomplicated pregnancies (normal group). Intima-media thickness (IMT) of the carotid artery was assessed as a proxy for maternal organ vascular disorder. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for hypoxia-inducible factor-1α (HIF-1α), which reflects hypoxic changes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which reflects oxidative DNA damage.Results: Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum sFlt-1 concentrations, ratio of sFlt-1/PlGF, and proportions of HIF-1α-positive nuclei and 8-OHdG-positive nuclei were significantly higher in the PE group compared to GH and normal groups. IMT was significantly greater in GH and PE groups compared to the normal group, and was higher in the GH group compared to the PE group.Conclusions: Our findings suggest that placental hypoxic changes and oxidative DNA damage are severe in patients with PE and accompanied by an increase in antiangiogenic factors. Moreover, maternal organ vascular disorder was more severe in patients with GH compared to those with PE, as assessed by IMT.Key message: PE is a two-stage disorder that involves uteroplacental dysfunction, and organic vascular disorder underlies GH.

Placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction.

OBJECTIVE: The purpose of this study was to investigate the relationship between placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction (FGR). METHODS: We examined serum concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and sFlt-1, placental oxidative DNA damage, and maternal endothelial function in 17 women with early-onset preeclampsia (PE), 18 with late-onset PE, 14 with normotensive FGR, and 21 controls. Flow-mediated vasodilation (FMD) was assessed as a marker of maternal endothelial function. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. RESULTS: Maternal serum d-ROM, sFlt-1 concentrations, and FMD did not significantly differ between the control and normotensive FGR groups. The proportion of nuclei staining positive for 8-OHdG was significantly higher in the normotensive FGR group relative to the control group. CONCLUSIONS: Our findings demonstrate that, despite the presence of placental oxidative DNA damage as observed in PE patients, pregnant women with normotensive FGR show no increase in the concentrations of sFlt-1 and d-ROMs, or a decrease in FMD.

Pregnancy-induced hypertension is associated with an increase in the prevalence of cardiovascular disease risk factors in Japanese women.

OBJECTIVE: This study assessed whether pregnancy-induced hypertension (PIH) affects the prevalence of cardiovascular disease (CVD) risk factors in later life among Japanese women. METHODS: Study participants were 1,185 women (mean [SD] age, 46.5 [5.6] y; range, 38-73 y) aged 40 years or older who underwent a health checkup at a periodic health examination facility between January 2012 and December 2013 and had experienced giving birth. Questionnaires were sent to potential participants, and they were encouraged to provide their Maternal and Child Health Handbook (handbook). We recruited 101 women with a history of PIH (PIH group) and 1,084 women with uncomplicated pregnancy at delivery (control group). Groupings were based on information from the handbook. We assessed the association between PIH and CVD in later life among Japanese women by focusing on hypertension, diabetes mellitus, and dyslipidemia as risk factors for CVD. Odds ratios (ORs) for the use of antihypertensive, diabetes mellitus, and dyslipidemic medications in the PIH group were determined. RESULTS: Women with PIH had increased risk of antihypertensive medication use compared with women without PIH (2.9% vs 13.9%; OR, 4.28; 95% CI, 2.14-8.57). Triglycerides were significantly higher and high-density lipoprotein cholesterol was significantly lower in the PIH group than in the control group. The OR for dyslipidemic medication use in the PIH group relative to the control group was 3.20 (95% CI, 1.42-7.22). CONCLUSIONS: Our findings suggest that a history of PIH may be associated with an increased risk of hypertension (a risk factor for CVD) in later life among Japanese women.

Differences in vascular reactivity between pregnant women with chronic hypertension and preeclampsia.

The purpose of this study was to evaluate the distinct pathogenic mechanisms underlying chronic hypertension in pregnancy and preeclampsia in terms of oxidative stress and vascular reactivity. A total of 17 women with uncomplicated pregnancies, 30 women with preeclampsia and 17 women with chronic hypertension were evaluated. We measured serum derivatives of reactive oxygen metabolites (d-ROMs; marker of oxygen free radicals), flow-mediated vasodilation (FMD; marker of endothelial function) and intima-media thickness in the carotid artery (IMT; marker of atherogenesis) during pregnancy and 1 month after delivery. Serum d-ROM concentrations were significantly higher in women with chronic hypertension and severe preeclampsia than in the control group during pregnancy. d-ROM concentrations in all groups significantly decreased to similar levels 1 month after delivery. FMD was significantly lower during pregnancy in preeclamptic and chronic hypertension groups compared with the control group. FMD in preeclamptic groups significantly increased and normalized to control levels after delivery. Similarly, FMD in the chronic hypertension group significantly increased after delivery but was still lower. IMT in the chronic hypertension group was significantly higher than that in control and preeclamptic groups. These findings suggest that endothelial dysfunction induced by enhanced oxidative stress is reversible in women with preeclampsia, whereas impaired vascular reactivity may be associated with atherosclerotic changes in women with chronic hypertension.

Differences in levels of oxidative stress in mothers and neonate: the impact of mode of delivery.

OBJECTIVE: To determine there are differences in the production levels of oxygen free radical between mothers and neonates by the mode of delivery, we measured oxygen free radical concentrations in maternal vein and umbilical artery. METHODS: Forty-four women with singleton term pregnancies were prospectively recruited and classified into two groups: those who had a spontaneous uncomplicated vaginal delivery (VD group; n = 21), and those who had an elective cesarean delivery (CD group; n = 23). We determined maternal and fetal oxidative stress levels by measuring concentrations of derivatives of reactive oxygen metabolites (d-ROMs) in maternal vein before delivery and on postnatal day 5, and in umbilical artery at delivery. We also measured the pH, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2) and base excess (BE) in umbilical artery blood collected at delivery. RESULTS: The concentrations of d-ROMs in maternal vein on postnatal day 5 were significantly decreased in the VD group, but were significantly increased in the CD group, compared to before delivery. The concentrations of d-ROMs in umbilical artery were significantly higher in the VD group than the CD group. Compared to the CD group, umbilical artery pH tended to be lower (p = 0.07), and BE significantly lower (p < 0.005), in the VD group. There were no significant differences in umbilical artery PaO2 and PaCO2 between the two groups. CONCLUSION: Our findings indicate that those production levels of oxygen free radical in mothers are greater by CD than by VD, while those in neonates are greater by VD than by CD.

Increased oxygen free radical production during pregnancy may impair vascular reactivity in preeclamptic women.

To determine whether enhanced oxidative stress during pregnancy impairs vascular endothelial function and improves after delivery in preeclamptic women, we measured serum parameters of oxidative stress and endothelial function during pregnancy and 1 month after delivery in women with or without preeclampsia. We evaluated 18 participants with uncomplicated pregnancies, 11 with mild preeclampsia and 13 with severe preeclampsia. The plasma concentrations of reactive oxygen metabolite derivatives (d-ROMs) were measured, and the biological antioxidant potential (BAP) was determined to evaluate the oxygen free radicals and antioxidants, respectively. Flow-mediated vasodilation (FMD) was also assessed as a marker of endothelial function. FMD was decreased significantly in both preeclamptic groups compared with control during pregnancy. FMD did not change after delivery in the control group, but it significantly increased after delivery in both the mildly and severely preeclamptic groups, nearing control levels 1 month after delivery (mild, 6.5±3.6-9.0±3.5%; severe, 4.3±3.3-9.7±2.6%). No changes in d-ROM concentrations were observed in the control group; however, the concentrations in both the mildly and severely preeclamptic groups significantly decreased to normal levels 1 month after delivery (mild, 562.0±106.5-430.5±90.5 CARR U (Carratelli units); severe, 681.0±239.0-411.8±69.7 CARR U). The plasma BAP levels did not change significantly in all three groups. A negative correlation between FMD and d-ROM concentrations was observed in the preeclamptic group, but not in the control group (r=-0.497; P<0.05). Our findings indicated that enhanced oxidative stress during pregnancy may impair endothelial function and improve after delivery in preeclamptic women.

PP043. Oxidative stress in the maternal body also affects the fetus in preeclamptic women with fetal growth restriction.

The purpose of the present study was to determine whether oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR. We ∥@consecutively recruited 17 preeclamptic women with FGR, 16 preeclamptic women without FGR, and 16 healthy pregnant women with uncomplicated pregnancy. We measured concentrations of derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxygen free radicals in a maternal vein, umbilical artery, and umbilical vein. ∥@Maternal d-ROM levels were higher in preeclamptic groups compared to the control group. Umbilical artery and vein d-ROM levels were elevated in preeclamptic women with FGR compared to the control group. Umbilical artery d-ROM levels were significantly higher than in the vein in preeclamptic women with FGR, but not in those without FGR. Umbilical arterial blood pH was significantly lower in preeclamptic women with FGR. The partial pressure of oxygen (PaO2) in umbilical arterial blood tended to be lower in preeclamptic women with FGR (p=0.08). The partial pressure of carbon dioxide (PaCO2) in umbilical arterial blood was significantly higher in preeclamptic women with FGR. These results indicate that oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR.

The severity of hypoxic changes and oxidative DNA damage in the placenta of early-onset preeclamptic women and fetal growth restriction.

OBJECTIVE: To investigate the relation between the severity of hypoxic changes and oxidative DNA damage in the placenta of early and late-onset preeclampic women and fetal growth restriction (FGR), serum parameters of oxidative stress, placental hypoxic change, and oxidative DNA damage were determined. METHODS: We examined 10 participants with uncomplicated pregnancies, 13 with early-onset and 12 with late-onset preeclampsia. Maternal and umbilical plasma derivatives of reactive oxygen metabolites (d-ROMs) were measured as markers of oxygen free radicals. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2'-deoxyguanosine (8-OHdG), redox factor-1 (ref-1), and hypoxia-induced factor-1α (HIF-1α), which are markers of oxidative DNA damage, repair functions, and hypoxia status, respectively. RESULTS: 8-OHdG was higher in both preeclamptic groups, but significantly higher in the early-onset preeclamptic group. Ref-1 was higher in the late-onset preeclamptic group. HIF-1α was higher in both preeclamptic groups, with a tendency towards a higher in the early-onset preeclamptic group. CONCLUSIONS: Our findings indicate that the severity of hypoxic changes and oxidative DNA damage are greater in the placenta of women with early-onset preeclampsia, and that the prolonged preeclamptic conditions may reduce placental blood flow, ultimately leading to FGR.

Increased oxidant generation in the metabolism of hypoxanthine to uric acid and endothelial dysfunction in early-onset and late-onset preeclamptic women.

OBJECTIVE: The purpose of this study was to evaluate the association of vascular endothelial dysfunction with increased oxidant generation in the metabolism of hypoxanthine to uric acid in early-onset compared to late-onset preeclampsia. METHODS: We investigated 12 women with early-onset preeclampsia, 14 women with late-onset preeclampsia, and 20 women with uncomplicated pregnancies. We measured serum derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxygen free radicals, serum biological antioxidant potential (BAP), hypoxanthine, uric acid, uric acid clearance (CUA), and flow-mediated vasodilation (FMD) as a marker of endothelial function in preeclamptic women. RESULTS: Concentration of d-ROMs was significantly higher in both preeclamptic groups compared to the control group. Plasma levels of uric acid were significantly elevated in both preeclamptic groups compared to the control group. Plasma levels of hypoxanthine were significantly higher in early-onset preeclamptic women compared to controls, but not in late-onset preeclamptic women. CUA was significantly lower in late-onset preeclamptic women compared to controls, but not in early-onset preeclamptic women. The concentrations of hypoxanthine and uric acid correlated positively with the concentration of d-ROMs in all pregnant women. FMD was significantly lower in both preeclamptic groups compared with controls, but FMD in the early-onset preeclamptic group was significantly lower than in the late-onset preeclamptic group. CONCLUSIONS: We found that increased oxidant generation during metabolism of hypoxanthine to uric acid may impair endothelial function in early-onset preeclampsia.

[Nonpharmacologic treatment for insomnia].

Nonpharmacologic treatment for insomnia occupies an important position on the treatment of insomnia. It is necessary to educate the patient on sleep hygiene to adjust the unappropriate sleep pattern. Within methods of relaxation, autonomy training and biofeedback method are methods using muscle relaxation to achieve psychological balance. Morita therapy is a method to accept insomnia as it is, and give guidance on the patient's life activity in a constructive way. It is important to listen carefully to the patient's life background and choose treatment based on that information. For this, an appropriate construction of a doctor-patient relationship is essential.

[Differential diagnosis of depressive state].

Depressive state is experienced usually in health subjects as "grief" process or "mourning work" in object loss. Also, subthreshold depression (sD) has been found to be a highly prevalent condition, with a considerable impact on the quality of life of patients, resulting in a strongly increased service utilization, and it has been found to be associated with large-scale economic costs because of disability days. A person can be considered to have sD when he or she has clinically relevant depressive symptoms, without meeting criteria for a full-blown major depressive disorder (MDD). The clinically relevant depressive symptoms in sD can either be operationalized as having a depressed mood with one or more additional symptoms of a mood disorder, or as meeting the criteria of minor depression (mD), as defined in the Appendix of the DSM-IV. Assessing the incidence of MDD in patients exhibiting sD is important for several reasons. First, it is an important indicator for the clinical relevance of sD. Secondly, it is important for understanding the process by which an individual develops MDD and the role of depressive symptoms in the process. Thirdly, the increased risk is important because it may provide a rationale for the development of new interventions that prevent the onset of new cases of MDD. Several recent studies in this area have found evidence that it is indeed possible to reduce the number of new cases of MDD by intervening in subjects with sD.