Is salivary uric acid, a putative biomarker of pre-eclampsia, of maternal, placental, or fetal origin?

OBJECTIVES: Increased salivary uric acid (sUA) represents a potential biomarker predictive of pre-eclampsia (PE), but its origin is unclear. The study explores whether sUA levels reflect maternal or feto-placental physiological stress and whether sUA levels in these cases correlate with amniotic fluid (fetal origin), maternal blood (maternal origin), or cord blood (fetal vs placental origin). STUDY DESIGN: Pregnant women (n = 39) undergoing amniotomy or caesarean section after 34 gestational weeks were designated into three groups of either maternal, feto-placental, or no signs of physiological stress: women (n = 15) in the established first phase of active labour and without any signs of fetal growth restriction (FGR) or PE were assigned to the maternal stress group, women (n = 6) with an ultrasound-based diagnosis of FGR, with or without PE, were assigned to the feto-placental stress group, and women (n = 18) not yet in active labour and without any signs of FGR or PE, were assigned to the control group. Uric acid levels in corresponding samples of amniotic fluid, saliva, maternal blood, and cord blood were compared between groups and between body compartments within each group. RESULTS: The feto-placental stress group showed increased UA levels in saliva (median, interquartile range [IQR]: 0.47 [0.38] mmol/L, P = 0.023) and maternal blood (0.42 [0.13] mmol/L, P = 0.032), but no differences in amniotic fluid or cord blood compared with the other groups. Within the control and maternal stress group, sUA levels were lower compared with maternal blood (0.20 [0.08] vs 0.25 [0.08] mmol/L, Pcontrol = 0.018; 0.20 [0.06] vs 0.26 [0.08] mmol/L, Pmaternal = 0.001) and highest in amniotic fluid (control group (0.49 [0.18] mmol/L): Pmaternal,blood = 0.001, Pumbilical,artery = <0.001, Pumbilical,vein = <0.001, Psaliva = <0.001) (maternal stress group (0.56 [0.23] mmol/L): Pmaternal,blood = 0.021, Pumbilical,artery = 0.006, Pumbilical,vein = 0.004, Psaliva = 0.003). Levels did not differ between compartments in the feto-placental stress group. CONCLUSIONS: Salivary and maternal blood UA levels were increased in the feto-placental stress group with salivary levels increasing more than blood levels compared with the maternal stress and control groups, whilst UA in amniotic fluid were not different between the groups, suggesting a placental origin and potential use of sUA as a biomarker of placental dysfunction, including FGR and severe PE.

Hypothyroidism and urinary incontinence: Prevalence and association in a Danish, female sample from the Lolland-Falster Health study.

INTRODUCTION: We aimed to estimate the prevalence of urinary incontinence (UI) in women with hypothyroidism and subclinical hypothyroidism and to examine the association of hypothyroidism and UI. METHODS: This cross-sectional study was based on the population-based Lolland-Falster Health Study (LOFUS), Denmark. Data comprising a questionnaire, physical examination, and blood samples were collected between 2016 and 2020. Multiple logistic regression was used to estimate odds ratios (OR) and control for possible confounders: age, body mass index, diabetes, smoking, and education. RESULTS: Of 7,699 women included in the study, 7.9% had hypothyroidism, and 2.4% had subclinical hypothyroidism. The prevalence of any UI in women with hypothyroidism, subclinical hypothyroidism, and a control group (normal level of thyroid hormones) was 43.6%, 38.1%, and 39.3%, respectively. After controlling for confounders, no association between hypothyroidism and any UI (OR 1.01, 95% CI 0.85-1.20) or frequent UI (OR 1.05, 95% CI 0.84-1.32) were demonstrated. Additional, no association between subclinical hypothyroidism and any UI (OR 0.87, 95% CI 0.64-1.18) or frequent UI (OR 1.15, 95 CI 0.79-1.69) were demonstrated. CONCLUSIONS: In our female sample, the prevalence of UI was high regardless of the thyroid status. No association between hypothyroidism and any or frequent UI was demonstrated. The prevalence of hypothyroidism was 7.9%.

Prevalence of urinary incontinence among women with diabetes in the Lolland-Falster Health Study, Denmark.

AIMS: To investigate the prevalence of urinary incontinence (UI) and UI subtypes (stress, urgency, and mixed UI) in women with or without diabetes mellitus; and to investigate the association between diabetes and UI (any and subtypes). METHODS: A cross-sectional study based on the Lolland-Falster, Denmark population-based health study. From 2016 to 2020, clinical measurement, questionnaires, and blood tests were collected. A total of 8563 women aged 18 or older were enrolled. Data analysis included 7906 women. UI was defined as any involuntary leakage of urine during the previous 4 weeks. Multiple logistic regression was used to adjust for confounders: age, body mass index, parity, physical activity, previous gestational diabetes, education, and smoking. RESULTS: UI prevalence was 50.3% in women with diabetes and 39.3% in women without diabetes. The unadjusted and adjusted odds ratio (OR) for UI in women with diabetes was OR 1.56 (95% confidence interval [CI], 1.27-1.92) and 1.11 (95% CI, 0.88-1.38), respectively. Mixed UI was associated with diabetes after controlling for confounders. A subgroup analysis found women using multiple antidiabetic medications had increased odds of UI, 2.75 (95% CI, 1.38-5.48), after controlling for confounders. CONCLUSION: The prevalence of UI in women with diabetes was higher than in women without diabetes. The odds of UI was 56% higher in women with diabetes compared with women without diabetes but the effect was attenuated when controlling for confounders and statistically significance was not achieved. For a subgroup using multiple antidiabetic medications, the risk of UI was higher than in women without diabetes.

Salivary uric acid as a predictive test of preeclampsia, pregnancy-induced hypertension and preterm delivery: A pilot study.

INTRODUCTION: There remains a need for a non-invasive, low-cost and easily accessible way of identifying women at risk of developing hypertensive disorders in pregnancy. This study evaluated the predictive value of longitudinal salivary uric acid measurement. MATERIAL AND METHODS: Pregnant women (n = 137) from 20 weeks of gestation were recruited at St Richards Hospital, Chichester, UK, for this prospective cohort study. Weekly samples of salivary uric acid were analyzed until delivery. Information regarding pregnancy and labor were obtained from the patient's record after delivery. Independent t tests were used to compare mean levels of salivary uric acid in women with hypertensive complications and adverse fetal outcomes with women with normal pregnancies. Main outcome measures were preeclampsia, pregnancy-induced hypertension, spontaneous preterm delivery and small-for-gestational-age babies. RESULTS: From 21 weeks of gestation until delivery, levels of salivary uric acid increased significantly in women who subsequently developed preeclampsia and pregnancy-induced hypertension compared with women with normal pregnancies (preeclampsia-mean at gestational age 21-24, 95% confidence interval [95% CI] [mean GA21-24 ): 108 [63-185] vs 47 (39-55) µmol/L; P = .005; pregnancy-induced hypertension-mean GA21-24 : 118 [54-258] vs 47 [39-55] µmol/L; P = .004). In women who had spontaneous preterm delivery, salivary uric acid levels increased significantly from 29 to 32 weeks of gestation compared with women with normal pregnancies (mean GA29-32 : 112 (57-221) vs 59 (50-71) µmol/L; P = .04). In women who had babies small-for-gestational-age <10th percentile and small-for-gestational-age <3rd percentile, differences in salivary uric acid levels were insignificant. CONCLUSIONS: Elevated levels of salivary uric acid precede the onset of preeclampsia, pregnancy-induced hypertension and preterm delivery. Salivary uric acid may prove to be an early biomarker of hypertensive complications of pregnancy and spontaneous preterm delivery.

Pelvic organ prolapse surgery after native tissue vault suspension at hysterectomy-A prospective cohort study.

OBJECTIVE: The effect of prophylactic vaginal vault suspension during hysterectomy in prevention of subsequent development of pelvic organ prolapse (POP) is unknown. We aimed to investigate incidences and risk of POP surgery in women who had undergone hysterectomy on benign indication with and without prophylactic suspension. STUDY DESIGN: We linked the national clinical Danish Hysterectomy and Hysteroscopy Database (DHHD) to administrative registries to assess data on all total hysterectomies (1 May 2012 to 31 December 2014), suspension methods, age, POP surgery, births, obstetric complications, prescriptions, socioeconomic- and vital status. Women undergoing total hysterectomy on non-prolapse and benign indication with no prior POP surgery were included and followed from hysterectomy to POP surgery, death/emigration or end of study period (maximum 2 years). Descriptive statistics, cumulative incidence curves and multivariable Cox proportional hazard models were fitted to assess the associated risk of POP in relation to prophylactic suspension. RESULTS: We included 7625 patients undergoing total hysterectomy; of these, 6538 (85.7%) were registered with prophylactic suspension during hysterectomy and 1087 (14.3%) women were specifically registered with no suspension in the DHHD. At baseline, women undergoing hysterectomy with suspension were on average 47.1 years of age (standard error SE 0.1) compared to 48.4 years (SE 0.3) in women with no suspension (p-value <0.0001). Moreover, women with suspension differed from their counterparts with no suspension with respect to geographical site of hysterectomy, hysterectomy method, parity and income. The cumulative risk of POP surgery after two years follow-up was 0.9% and 0.5% in the suspension group and the no suspension group, respectively. In the adjusted analysis, we found no association of prophylactic suspension and risk of POP surgery, hazard ratio (HR) = 2.1 (95% confidence interval (CI) 0.8-5.3, p-value 0.13). CONCLUSION: Of all women undergoing hysterectomy for benign indication, 0.84% (N = 64) were surgically treated for POP. At two-year follow-up, there was no association between prophylactic vaginal vault suspension at time of hysterectomy and subsequent POP surgery.

A novel method to isolate retinal and brain microvessels from individual rats: Microscopic and molecular biological characterization and application in hyperglycemic animals.

Alterations in the retinal microvessel (RMV) compartment occurring in systemic disease states such as diabetes may eventually contribute to blindness. To specifically address the pathophysiological role of the microvasculature we developed a new method for RMV bulk isolation from individual rats. The extraction procedure performed in the cold throughout takes less than one hour. Slight modifications enable isolation of brain microvessels (BMVs) for comparison. Microscopically, RMVs and BMVs consisted mainly of capillaries of good structural integrity. The endothelial cell/pericyte ratio was approximately 1.8 in RMVs and 2.7 in BMVs, well in agreement with data from intact vascular beds. Total RNA extracted from individual rats amounted to approximately 7 ng in RMVs, 50 ng in BMVs, and 155 ng in pial arteries (which were also isolated) with highly preserved integrity throughout. Measurements using microfluidic card methodology revealed segregation of RMVs, BMVs, and pial arteries in distinct clusters based on principal component analysis. In all three vascular compartments endothelial cell-specific markers were significantly enriched. Similarly, pericyte-specific markers displayed accumulation in RMVs, BMVs, and pial arteries, the latter probably reflecting the common ontogenetic origin of pericytes and smooth muscle cells. Isolation of RMVs, BMVs, and pial arteries from rats suffering from 8-weeks hyperglycemia yielded expression patterns of endothelial cell- and pericyte-specific marker genes largely comparable to those obtained in control rats. Our newly developed protocols allow for selective studies of RMVs from individual rats to characterize reactive pathways, in comparison with the ontogenetically closely related BMVs. Moreover, our protocols with inclusion of pial arteries enable comparative studies of the macro- and microvasculature from the same organ.

No evidence of association between native tissue vault suspension and risk of pelvic pain or sexual dysfunction.

OBJECTIVE: Hysterectomy is suspected of increasing risk of subsequent pelvic organ prolapse (POP). In attempt to prevent this, several suspension methods during hysterectomy on benign indication are used as a prophylactic procedure. However, possible complications to the use of prophylactic vaginal vault suspension to prevent POP are not fully investigated. We aimed to elucidate prophylactic vaginal vault suspension as a possible cause for pelvic pain and sexual dysfunction. STUDY DESIGN: We included all women registered with a total hysterectomy on benign indication and registered with a suspension method or specifically no suspension in the nationwide Danish Hysterectomy and Hysteroscopy Database (DHHD) between 10 May 2012 and 4 September 2013 (N = 3999). A postal questionnaire on pelvic pain and sexual dysfunction was sent to women 25.8 (range 23.8-28.4) months after hysterectomy. Questions were selected from a previous study as well as from the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). We used independent samples t-tests and χ2-tests for univariate analyses. In multivariable analyses, we used log-binomial - and linear regression models adjusted for risk factors of pelvic pain and sexual dysfunction, respectively. RESULTS: The response rate was 60.3% (N = 2412). Of the respondents, 88.8% (N = 2143) were registered with a suspension method and 11.2% (N = 269) were registered with specifically no suspension. Overall, pelvic pain of any kind was reported in 24.3% (N = 576) of the respondents. In adjusted log-binomial regression, suspension did not increase risk of pelvic pain compared to no suspension (RR 0.92; 95% CI 0.75 to 1.14; p-value 0.45). In adjusted linear regression, suspension was significantly associated with less degree of sexual dysfunction (regression coefficient -0.92; 95% CI -1.70 to -0.14; p-value 0.02). CONCLUSIONS: In women undergoing prophylactic vaginal vault suspension during hysterectomy, we found less sexual dysfunction and no evidence of increased risk of pelvic pain compared to women with no vaginal vault suspension.

Vaginal vault suspension during hysterectomy for benign indications: a prospective register study of agreement on terminology and surgical procedure.

INTRODUCTION AND HYPOTHESIS: Several suspension methods are used to try to prevent pelvic organ prolapse (POP) after hysterectomy. We aimed to evaluate agreement on terminology and surgical procedure of these methods. METHODS: We randomly chose 532 medical records of women with a history of hysterectomy from the Danish Hysterectomy and Hysteroscopy Database (DHHD). Additionally, we video-recorded 36 randomly chosen hysterectomies. The hysterectomies were registered in the DHHD. The material was categorized according to predefined suspension methods. Agreement compared suspension codes in DHHD (gynecologists' registrations) with medical records (gynecologists' descriptions) and with videos (reviewers' categorizations) respectively. Whether the vaginal vault was suspended (pooled suspension) or not (no suspension method + not described) was analyzed, in addition to each suspension method. RESULTS: Regarding medical records, agreement on terminology was good among patients undergoing pooled suspension in cases of hysterectomy via the abdominal and vaginal route (agreement 78.7, 92.3%). Regarding videos, agreement on surgical procedure was good among pooled suspension patients in cases of hysterectomy via the abdominal, laparoscopic, and vaginal routes (agreement 88.9, 97.8, 100%). Agreement on individual suspension methods differed regarding both medical records (agreement 0-90.1%) and videos (agreement 0-100%). CONCLUSIONS: Agreement on terminology and surgical procedure regarding suspension method was good in respect of pooled suspension. However, disagreement was observed when individual suspension methods and operative details were scrutinized. Better consensus of terminology and surgical procedure is warranted to enable further research aimed at preventing POP among women undergoing hysterectomy.

Perivascular tissue inhibits rho-kinase-dependent smooth muscle Ca(2+) sensitivity and endothelium-dependent H2 S signalling in rat coronary arteries.

Interactions between perivascular tissue (PVT) and the vascular wall modify artery tone and contribute to local blood flow regulation. Using isometric myography, fluorescence microscopy, membrane potential recordings and phosphospecific immunoblotting, we investigated the cellular mechanisms by which PVT affects constriction and relaxation of rat coronary septal arteries. PVT inhibited vasoconstriction to thromboxane, serotonin and α1 -adrenergic stimulation but not to depolarization with elevated extracellular [K(+) ]. When PVT was wrapped around isolated arteries or placed at the bottom of the myograph chamber, a smaller yet significant inhibition of vasoconstriction was observed. Resting membrane potential, depolarization to serotonin or thromboxane stimulation, and resting and serotonin-stimulated vascular smooth muscle [Ca(2+) ]-levels were unaffected by PVT. Serotonin-induced vasoconstriction was almost abolished by rho-kinase inhibitor Y-27632 and modestly reduced by protein kinase C inhibitor bisindolylmaleimide X. PVT reduced phosphorylation of myosin phosphatase targeting subunit (MYPT) at Thr850 by ∼40% in serotonin-stimulated arteries but had no effect on MYPT-phosphorylation in arteries depolarized with elevated extracellular [K(+) ]. The net anti-contractile effect of PVT was accentuated after endothelial denudation. PVT also impaired vasorelaxation and endothelial Ca(2+) responses to cholinergic stimulation. Methacholine-induced vasorelaxation was mediated by NO and H2 S, and particularly the H2 S-dependent (dl-propargylglycine- and XE991-sensitive) component was attenuated by PVT. Vasorelaxation to NO- and H2 S-donors was maintained in arteries with PVT. In conclusion, cardiomyocyte-rich PVT surrounding coronary arteries releases diffusible factors that reduce rho-kinase-dependent smooth muscle Ca(2+) sensitivity and endothelial Ca(2+) responses. These mechanisms inhibit agonist-induced vasoconstriction and endothelium-dependent vasorelaxation and suggest new signalling pathways for metabolic regulation of blood flow.

Plasma YKL-40 during pregnancy and gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is characterised by hyperglycaemia during pregnancy. The clinical circumstances involved in the development of GDM leaves the patient at a high risk of the subsequent development of type 2 diabetes. Plasma levels of the inflammation marker YKL-40 are elevated in type 2 diabetes and correlate with fasting plasma glucose levels and insulin resistance in patients with type 2 diabetes. With the present study we aimed to determine if pregnancy (and associated insulin resistance) with or without GDM affects plasma YKL-40 levels. Plasma from women diagnosed with GDM and healthy normal glucose-tolerant pregnant women (non-GDM) was obtained at the third trimester of pregnancy and again 3-4 months following delivery, and levels of YKL-40 and interleukin 6 (IL-6; known to regulate YKL-40) were measured. Plasma YKL-40 levels were similarly low during pregnancy in both groups and increased significantly after delivery, but remained lower in the GDM group compared with the non-GDM group postpartum. In contrast, plasma IL-6 levels were not affected by pregnancy or diagnosis of GDM, Nevertheless, YKL-40 levels were associated with IL-6 levels in the non-GDM group (but not in the GDM group). Pregnancy seems to be associated with a temporary reduction in circulating YKL-40, which increases after delivery, but to a much lesser extent in women with GDM than in non-GDM women.

Increased mortality associated with low use of clopidogrel in patients with heart failure and acute myocardial infarction not undergoing percutaneous coronary intervention: a nationwide study.

OBJECTIVES: We studied the association of clopidogrel with mortality in acute myocardial infarction (AMI) patients with heart failure (HF) not receiving percutaneous coronary intervention (PCI). BACKGROUND: Use of clopidogrel after AMI is low in patients with HF, despite the fact that clopidogrel is associated with absolute mortality reduction in AMI patients. METHODS: All patients hospitalized with first-time AMI (2000 through 2005) and not undergoing PCI within 30 days from discharge were identified in national registers. Patients with HF treated with clopidogrel were matched by propensity score with patients not treated with clopidogrel. Similarly, 2 groups without HF were identified. Risks of all-cause death were obtained by the Kaplan-Meier method and Cox regression analyses. RESULTS: We identified 56,944 patients with first-time AMI. In the matched cohort with HF (n = 5,050) and a mean follow-up of 1.50 years (SD = 1.2), 709 (28.1%) and 812 (32.2%) deaths occurred in patients receiving and not receiving clopidogrel treatment, respectively (p = 0.002). The corresponding numbers for patients without HF (n = 6,092), with a mean follow-up of 2.05 years (SD = 1.3), were 285 (9.4%) and 294 (9.7%), respectively (p = 0.83). Patients with HF receiving clopidogrel demonstrated reduced mortality (hazard ratio: 0.86; 95% confidence interval: 0.78 to 0.95) compared with patients with HF not receiving clopidogrel. No difference was observed among patients without HF (hazard ratio: 0.98; 95% confidence interval: 0.83 to 1.16). CONCLUSIONS: Clopidogrel was associated with reduced mortality in patients with HF who do not undergo PCI after their first-time AMI, whereas this association was not apparent in patients without HF. Further studies of the benefit of clopidogrel in patients with HF and AMI are warranted.