Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development.

Requirements for vesicle fusion within the heart remain poorly understood, despite the multitude of processes that necessitate proper intracellular trafficking within cardiomyocytes. Here, we show that Syntaxin 4 (STX4), a target-Soluble N-ethylmaleimide sensitive factor attachment receptor (t-SNARE) protein, is required for normal vertebrate cardiac conduction and vesicular transport. Two patients were identified with damaging variants in STX4. A patient with a homozygous R240W missense variant displayed biventricular dilated cardiomyopathy, ectopy, and runs of non-sustained ventricular tachycardia, sensorineural hearing loss, global developmental delay, and hypotonia, while a second patient displayed severe pleiotropic abnormalities and perinatal lethality. CRISPR/Cas9-generated stx4 mutant zebrafish exhibited defects reminiscent of these patients' clinical presentations, including linearized hearts, bradycardia, otic vesicle dysgenesis, neuronal atrophy, and touch insensitivity by 3 days post fertilization. Imaging of Vamp2+ vesicles within stx4 mutant zebrafish hearts showed reduced docking to the cardiomyocyte sarcolemma. Optical mapping of the embryonic hearts coupled with pharmacological modulation of Ca2+ handling together support that zebrafish stx4 mutants have a reduction in L-type Ca2+ channel modulation. Transgenic overexpression of zebrafish Stx4R241W, analogous to the first patient's STX4R240W variant, indicated that the variant is hypomorphic. Thus, these data show an in vivo requirement for SNAREs in regulating normal embryonic cardiac function and that variants in STX4 are associated with pleiotropic human disease, including cardiomyopathy.

Effects of Foliar Application of ZnO Nanoparticles on Lentil Production, Stress Level and Nutritional Seed Quality under Field Conditions.

Nanotechnology offers new opportunities for the development of novel materials and strategies that improve technology and industry. This applies especially to agriculture, and our previous field studies have indicated that zinc oxide nanoparticles provide promising nano-fertilizer dispersion in sustainable agriculture. However, little is known about the precise ZnO-NP effects on legumes. Herein, 1 mg·L-1 ZnO-NP spray was dispersed on lentil plants to establish the direct NP effects on lentil production, seed nutritional quality, and stress response under field conditions. Although ZnO-NP exposure positively affected yield, thousand-seed weight and the number of pods per plant, there was no statistically significant difference in nutrient and anti-nutrient content in treated and untreated plant seeds. In contrast, the lentil water stress level was affected, and the stress response resulted in statistically significant changes in stomatal conductance, crop water stress index, and plant temperature. Foliar application of low ZnO-NP concentrations therefore proved promising in increasing crop production under field conditions, and this confirms ZnO-NP use as a viable strategy for sustainable agriculture.

Effect of Foliar Spray Application of Zinc Oxide Nanoparticles on Quantitative, Nutritional, and Physiological Parameters of Foxtail Millet (Setaria italica L.) under Field Conditions.

It has been shown that the foliar application of inorganic nano-materials on cereal plants during their growth cycle enhances the rate of plant productivity by providing a micro-nutrient source. We therefore studied the effects of foliarly applied ZnO nanoparticles (ZnO NPs) on Setaria italica L. foxtail millet's quantitative, nutritional, and physiological parameters. Scanning electron microscopy showed that the ZnO NPs have an average particle size under 20 nm and dominant spherically shaped morphology. Energy dispersive X-ray spectrometry then confirmed ZnO NP homogeneity, and X-ray diffraction verified their high crystalline and wurtzite-structure symmetry. Although plant height, thousand grain weight, and grain yield quantitative parameters did not differ statistically between ZnO NP-treated and untreated plants, the ZnO NP-treated plant grains had significantly higher oil and total nitrogen contents and significantly lower crop water stress index (CWSI). This highlights that the slow-releasing nano-fertilizer improves plant physiological properties and various grain nutritional parameters, and its application is therefore especially beneficial for progressive nanomaterial-based industries.

High-dose density neoadjuvant chemotherapy in bulky IB cervical cancer.

OBJECTIVE: The endpoint of this prospective study is to evaluate response rate, survival and toxicity of high-dose density neoadjuvant chemotherapy (NAC) in bulky IB cervical cancer. MATERIAL AND METHODS: Between January 1998 and December 2009, 154 women were enrolled into study. Three patients were withdrawn. Of the 151 women, 119 had stage IB2 cervical cancer (78.8%) and 32 had stage IB1 cancer (21.2%) infiltrating the whole cervical stroma. Women received 3-4cycle cisplatin-75mg/m(2) and ifosfamide-2g/m(2) in cases of squamous-cell cancer or cisplatin-75mg/m(2) and doxorubicin-35mg/m(2) in adenocarcinoma every 10days and then underwent radical hysterectomy type III. Patients who had non-resectable disease underwent chemoradiotherapy. RESULTS: The overall response rate (reduction of tumor volume more than 50%) was 78.8%. Reduction of tumor volume less than 50% was seen in 15.2%. Tumor progression during chemotherapy occurred in nine patients (6.0%). There were positive lymph-nodes in 26 patients (18.3%) of the 142 that underwent surgery. 38 women underwent adjuvant radiotherapy (26.7%). There were 26 recurrences (17.2%). After surgery 20 women recurred from 142 (14.1%) and after primary radiotherapy 6 from 9 women recurred (66.7%). 25 of 151 women died from disease (16.5%). At the time of the study, surgery was performed in 118 women 5 or more years ago, 19 of them died of disease. Five-year specific survival is 83.6%. Grade 3-4 neutropenia was found in only 7.3% of the women, and grade 3-4 thrombocytopenia were found in 1.3%. CONCLUSION: High-dose density NAC appears to be feasible in the treatment IB bulky cervical cancer and toxicity is acceptable. Adjuvant radiotherapy was used only in 26.7%.

Surgical options in early cervical cancer.

Cancer of the cervix is the second most common cancer in women worldwide and the fourth leading cause of cancer mortality in women. Early cervical cancer stage IB1 includes a broad range of disease from clinically undetectable microinvasive cancer to bulky tumours that infiltrated the entire cervix. This article reviews the literature about risk factors and surgical radicality and fertility-sparing surgery in early cervical cancer. The review evaluates selection criteria, preoperative management and the most frequent surgical procedures used for individually tailored surgery for cervical cancer.