B-flow/spatiotemporal image correlation M-mode ultrasound provides novel method to quantify spiral artery remodeling during normal human pregnancy.

OBJECTIVES: During human pregnancy placental extravillous trophoblasts replace the vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling these arteries into distensible low resistance vessels to promote placental perfusion. The present study, determined whether B-flow/ spatio-temporal image correlation (STIC) M-mode ultrasonography provides an in vivo imaging method to digitally quantify spiral artery luminal distensibility, as a physiological index of spiral artery remodeling, during advancing stages of normal human pregnancy. METHODS: A prospective longitudinal observational study was conducted to quantify spiral artery distensibility, i.e. vessel luminal diameter at systole minus diameter at diastole, by B-flow/STIC M-mode ultrasonography during the first, second and third trimesters in 290 women exhibiting normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1), growth factors that modulate events important in spiral artery remodeling, were quantified in a subset of the subjects at the first, second and third semesters. RESULTS: Median [first quartile, third quartile] spiral artery distensibility progressively increased (P < 0.0001) between the first trimester (0.17 [0.14, 0.21]), second (0.23 [0.18, 0.28]) and third (0.26 [0.21, 0.35]) trimesters of pregnancy. Spiral artery volume flow (ml/cardiac cycle) progressively increased (P < 0.001) between the first 2.49 [1.38, 4.99], second 3.86 [2.06, 6.91] and third 7.79 [3.83, 14.98] trimesters. Coinciding with the elevation in spiral artery distensibility, the median ratio of serum PlGF/sFlt-1 levels increased (P < 0.001) between the first (7.2 [4.5, 10], second (22.7 [18.6, 42.2]) and third (56.2 [41.9, 92.5] trimesters. CONCLUSIONS: The present study shows that B-flow/STIC M-mode ultrasonography provides an in vivo imaging technology to digitally quantify structural/physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. This article is protected by copyright. All rights reserved.

The effect of obesity-related allostatic changes on cardio-metabolic risk in euthyroid children.

PURPOSE: The hormonal thyroid changes related to obesity, even when in the euthyroid state, may contribute to the unfavorable cardio-metabolic profile of obese patients. In this retrospective study, we aim to investigate the biochemical thyroid changes and the association between serum TSH, FT4, FT3 and cardio-metabolic risk factors in euthyroid obese youths. METHODS: Four hundred ninety-one Caucasian euthyroid obese children and adolescents aged 9.93 ± 2.90 years were recruited. Each patient underwent clinical and auxological examination and laboratory workup including an OGTT and the measurement of thyroid function and lipid profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio, total cholesterol to HDL ratio, atherogenic index of plasma, insulinogenic index, area under the glucose and insulin curves were calculated. RESULTS: We found that TSH was positively correlated with BMI-SDS values and significantly associated with hypercholesterolemia and hyperinsulinemia; FT4 resulted negatively correlated with BMI-SDS; FT3 was positively correlated with BMI-SDS and the area under the curve of insulin and negatively correlated with HDL. FT3 and FT4 resulted significantly associated with severe obesity. In addition, children with high-normal TSH values showed higher triglyceride to high-density lipoprotein cholesterol ratio values than those with normal TSH levels. CONCLUSIONS: Our data showed that thyroid hormones could influence obesity, lipid and glycemic parameters in euthyroid youths. These findings could carry implications regarding optimal TSH levels in obese children and confirm the importance of evaluating the thyroid function as possible adjunctive cardio-metabolic risk factor related to obesity.

B-flow/spatiotemporal image correlation M-mode: novel ultrasound method that detects decrease in spiral artery luminal diameter in first trimester in primate model of impaired spiral artery remodeling.

OBJECTIVE: To determine if B-flow/spatiotemporal image correlation (STIC) M-mode ultrasonography detects a decrease in spiral artery luminal diameter and volume flow during the first trimester in a non-human primate model of impaired spiral artery remodeling (SAR). METHODS: Pregnant baboons were treated daily with estradiol benzoate on days 25-59 of the first trimester (term, 184 days), or remained untreated. On day 60 of gestation, spiral artery luminal diameter (in seven untreated and 12 estradiol-treated baboons) and volume flow (in four untreated and eight estradiol-treated baboons) were quantified by B-flow/STIC M-mode ultrasonography. In addition, in 15 untreated and 18 estradiol-treated baboons, the percent of spiral arteries remodeled by extravillous trophoblasts was quantified ex vivo by immunohistochemical image analysis on placental basal plate tissue collected via Cesarean section on day 60. Findings were compared between treated and untreated animals. The correlation between spiral artery luminal diameter and percent of SAR was assessed in three untreated and six estradiol-treated baboons which underwent both B-flow/STIC M-mode ultrasound and quantification of SAR. RESULTS: The proportion of spiral arteries greater than 50 µm in diameter remodeled by extravillous trophoblasts was 70% lower in estradiol-treated baboons than in untreated animals (P = 0.000001). Spiral artery luminal diameter in systole and diastole, as quantified by B-flow/STIC M-mode in the first trimester of pregnancy, was 31% (P = 0.014) and 50% (P = 0.005) lower, respectively, and volume flow was 85% lower (P = 0.014), in SAR-suppressed baboons compared with untreated animals. There was a significant correlation between spiral artery luminal diameter as quantified by B-flow/STIC M-mode ultrasonography and the percent of SAR (P < 0.05). CONCLUSION: B-flow/STIC M-mode ultrasonography provides a novel real-time non-invasive method to detect a decrease in uterine spiral artery luminal diameter and volume flow during the cardiac cycle, reflecting decreased distensibility of the vessel wall, in the first trimester in a non-human primate model of defective SAR. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Curcumin dietary supplementation ameliorates disease phenotype in an animal model of Huntington's disease.

Huntington's disease (HD) has traditionally been described as a disorder purely of the brain; however, evidence indicates that peripheral abnormalities are also commonly seen. Among others, severe unintended body weight loss represents a prevalent and often debilitating feature of HD pathology, with no therapies available. It correlates with disease progression and significantly affects the quality of life of HD patients. Curcumin, a naturally occurring polyphenol with multiple therapeutic properties, has been validated to exert important beneficial effects under health conditions as well as in different pathological settings, including neurodegenerative and gastrointestinal (GI) disorders. Here, we investigated the potential therapeutic action that curcumin-supplemented diet may exert on central and peripheral dysfunctions in R6/2 mice, a well-characterized HD animal model which recapitulates some features of human pathology. Maintenance of normal motor function, protection from neuropathology and from GI dysfunction and preservation of GI emptying and conserved intestinal contractility, proved the beneficial role of life-long dietary curcumin in HD and corroborated the potential of the compound to be exploited to alleviate very debilitating symptoms associated with the disease.

Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

Emerging evidence indicates that Huntington's disease (HD) may be described as multi-organ pathology. In this context, we and others have contributed to demonstrate that the disease is characterized by an impairment of the homeostasis of gastro-intestinal (GI) tract. Sphingolipids represent a class of molecules involved in the regulation and maintenance of different tissues and organs including GI system. In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally in R6/2 HD mice. Our findings indicate, for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the potential to counteract the peripheral disturbances which may usually complicate the management of the disease and affect patient's quality of life.

Observational study on preoperative surgical field disinfection: povidone-iodine and chlorhexidine-alcohol.

BACKGROUND AND OBJECTIVES: Surgical site infection (SSI) rate is reported to range around 16%. Preoperative skin disinfection is keystone for SSI reduction. Chlorhexidine-alcohol has been reported to be more effective than Povidone-iodine (PVI). However, in many countries established habits and the inferior costs of PVI restrain the employment of chlorhexidine disinfection kits (ChloraPrep®) for the preparation of the surgical field. MATERIALS AND METHODS: The costs of surgical field preparation in clean-contaminated surgery utilizing PVI (Betadine) and chlorhexidine alcohol and the evaluation of surgeon compliance and satisfaction, were studied by a observational study on 50 surgical operations in which surgical field was prepared with PVI checking established guidelines, and on 50 surgical operations in which chlorhexidine-alcohol (ChloraPrep) was employed. The use of auxiliary material was tabulated as well as the timing of the phases of disinfection and the surgeon's opinions. RESULTS: The use of auxiliary material (gloves, gauzes, paper towels, surgical instruments, small swabs for umbilical cleaning) is associated with the type of disinfectant, with major use of auxiliary materials recorded in PVI disinfection. PVI disinfection does not follow stringent guidelines, in particular waiting for the disinfectant to dry. PVI guidelines are more demanding than those relative to ChloraPrep. The time necessary for the preparation of the field is significantly longer for PVI. Auxiliary material and guideline compliance must be taken into account when calculating costs; the former are direct costs (even though marginal) and the latter can determine major infective risk. CONCLUSIONS: Chlorhexidine in kits is easier and faster to use than PVI, requires less auxiliary material and has been shown previously to reduce SSI in clean contaminated surgery.

An economic evaluation of Clostridium difficile infection management in an Italian hospital environment.

BACKGROUND AND OBJECTIVES: Clostridium difficile infection (CDI) accounts for the majority of nosocomial cases of diarrhea, and with recent upsurge of multidrug-resistant strains, morbidity and mortality have increased. Data on clinical impact of CDI come mostly from Anglo-Saxon countries, while in Italy only two studies address the issue and no economic data exist on costs of CDI in the in hospital setting. A retrospective cross-sectional study with pharmacoeconomic analysis was performed on the CDI series of the Policlinico Gemelli of Rome, a major 1400 bed Hospital. PATIENTS AND METHODS: The clinical charts of 133 patients in a 26 month period were reviewed. All costs of the involved resources were calculated and statistical analysis was carried out with means and standard deviations, and categorical variables as number and percentages. RESULTS: The results show the significant sanitary costs of CDI in an Italian hospital setting. The cost analysis of the various elements (exams, imaging studies, therapies, etc.) shows that none independently influences the high cost burden of CDI, but that it is the simple length of hospital stay that represents the most important factor. CONCLUSIONS: Prevention of CDI is the most cost-effective approach. The major break-through in cost reduction of CDI would be a therapeutical intervention or procedure that shortens hospital length of stay.

Artificial intelligence methods enhance the discovery of RNA interactions.

Understanding how RNAs interact with proteins, RNAs, or other molecules remains a challenge of main interest in biology, given the importance of these complexes in both normal and pathological cellular processes. Since experimental datasets are starting to be available for hundreds of functional interactions between RNAs and other biomolecules, several machine learning and deep learning algorithms have been proposed for predicting RNA-RNA or RNA-protein interactions. However, most of these approaches were evaluated on a single dataset, making performance comparisons difficult. With this review, we aim to summarize recent computational methods, developed in this broad research area, highlighting feature encoding and machine learning strategies adopted. Given the magnitude of the effect that dataset size and quality have on performance, we explored the characteristics of these datasets. Additionally, we discuss multiple approaches to generate datasets of negative examples for training. Finally, we describe the best-performing methods to predict interactions between proteins and specific classes of RNA molecules, such as circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), and methods to predict RNA-RNA or RNA-RBP interactions independently of the RNA type.

Evaluation of potential miRNA sponge effects of SARS genomes in human.

To date the coronavirus family is composed of seven different viruses which were commonly known as cold viruses until the appearance of the severe acute respiratory coronavirus (SARS-CoV) in 2002, the middle east respiratory syndrome coronavirus (MERS) in 2012 and the severe acute respiratory coronavirus 2 (SARS-CoV-2) which caused the COVID-19 global pandemic in 2019. Using bioinformatic approaches we tested the potential interactions of human miRNAs, expressed in pulmonary epithelial cells, with the available coronavirus genomes. Putative miRNA binding sites were then compared between pathogenic and non pathogenic virus groups. The pathogenic group shares 6 miRNA binding sites that can be potentially involved in the sequestration of miRNAs already known to be associated with deep vein thrombosis. We then analysed ∼100k SARS-CoV-2 variant genomes for their potential interaction with human miRNAs and this study highlighted a group of 97 miRNA binding sites which is present in all the analysed genomes. Among these, we identified 6 miRNA binding sites specific for SARS-CoV-2 and the other two pathogenic viruses whose down-regulation has been seen associated with deep vein thrombosis and cardiovascular diseases. Interestingly, one of these miRNAs, namely miR-20a-5p, whose expression decreases with advancing age, is involved in cytokine signaling, cell differentiation and/or proliferation. We hypothesize that depletion of poorly expressed miRNA could be related with disease severity.

Acute intestinal ischemia in patients with COVID-19: single-centre experience and literature review.

OBJECTIVE: Acute Intestinal ischemia (AII) may involve the small and/or large bowel after any process affecting intestinal blood flow. COVID-19-related gastrointestinal manifestations, including AII, have been attributed to pharmacologic effects, metabolic disorders in ICU patients and other opportunistic colonic pathogens. AII in COVID-19 patients may be due also to "viral enteropathy" and  SARS-CoV-2-induced small vessel thrombosis. A critical appraisal of personal experience regarding COVID-19 and AII was carried out comparing this with a systematic literature review of published series. PATIENTS AND METHODS:   A retrospective observational clinical cohort study and a systematic literature review including only COVID-19 positive patients with acute arterial or venous intestinal ischemia were performed. The primary endpoint of the study was the mortality rate. Secondary endpoints were occurrence of major complications and length of hospital stay. RESULTS: Patient mean age was 62.9±14.9, with a prevalence of male gender (23 male, 72% vs. 9 female, 28%). The mean Charlson Comorbidity Index was 3.1±2.7. Surgery was performed in 24/32 patients (75.0%), with a mean delay time from admission to surgery of 6.0 ±5.6 days. Small bowel ischemia was confirmed to be the most common finding at surgical exploration (22/24, 91.7%). Acute abdomen at admission to the ED (Group 1) was observed in 10 (31.2%) cases, while 16 (50%) patients developed an acute abdomen condition during hospitalization (Group 2) for SARS-CoV-2 infection. CONCLUSIONS: Our literature review showed how intestinal ischemia in patients with SARS-CoV-2 has been reported all over the world. The majority of the patients have a high CCI with multiple comorbidities, above all hypertension and cardiovascular disease. GI symptoms were not always present at the admission. A high level of suspicion for intestinal ischemia should be maintained in COVID-19 patients presenting with GI symptoms or with incremental abdominal pain. Nevertheless, a prompt thromboelastogram and laboratory test may confirm the need of improving and fastening the use of anticoagulants and trigger an extended indication for early abdominal CECT in patients with suggestive symptoms or biochemical markers of intestinal ischemia.

How to define a quadruple aim framework to assess value in critical pathway of the patients with Clostridioides difficile infection.

OBJECTIVE: The study aims to define the set of Key Performance Indicators (KPIs) required to assess the Value delivered by managing patients with Clostridioides difficile infection through a Critical Pathway. We used the quadruple aim Value-Based approach, and we validated the set of KPIs with the Delphi method. MATERIALS AND METHODS: The study focuses on patients on board a Critical Pathway on Clostridioides difficile Infection and targeted towards a Fecal Microbiota Transplantation (FMT). FMT has been used to successfully treat recurrent Clostridium difficile infection. A two-round e-Delphi survey collecting data was conducted in 2019-2020 to validate the Value-Based evaluation tool. The Value-Based criteria taken into account are Clinical Outcomes, Experience of Care, Per-capita cost, Physician's burnout. RESULTS: The two rounds led to the validation of 50 items, and four primary clinical outcomes (Mortality rate, length of stay, readmission and complications related to the illness). CONCLUSIONS: The evaluation tool included is validated in its totality and can provide a comprehensive overview of the Value created by the Critical pathway for patients with Clostridioides difficile. We can extend the approach illustrated in this study can also to evaluate other Critical pathways.

The impact of SST2 trafficking and signaling in the treatment of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (Pan-NETs), are heterogeneous neoplasms, whose incidence and prevalence are increasing worldwide. Pan-NETs are characterized by the expression of somatostatin receptors (SSTs). In particular, SST2 is the most widely distributed SST in NETs, thus representing the main molecular target for somatostatin analogs (SSAs). SSAs are currently approved for the treatment of well-differentiated NETs, and radionuclide-labeled SSAs are used for diagnostic and treatment purposes. SSAs, by binding to SSTs, have been shown to inhibit hormone secretion and thus provide control of hypersecretion symptoms, when present, and inhibit tumor proliferation. After SSA binding to SST2, the fate of the receptor is determined by trafficking mechanisms, crucial for the response to endogenous or pharmacological ligands. Although SST2 acts mostly through G protein-dependent mechanism, receptor-ligand complex endocytosis and receptor trafficking further regulate its function. SST2 mediates the decrease of hormone secretion via a G protein-dependent mechanism, culminating with the inhibition of adenylyl cyclase and calcium channels; it also inhibits cell proliferation and increases apoptosis through the modulation of protein tyrosine phosphatases. Moreover, SST2 inhibits angiogenesis and cell migration. In this respect, the cross-talk between SST2 and its interacting proteins, including Filamin A (FLNA) and aryl hydrocarbon receptor-interacting protein (AIP), plays a crucial role for SST2 signaling and responsiveness to SSAs. This review will focus on recent studies from our and other groups that have investigated the trafficking and signaling of SST2 in Pan-NETs, in order to provide insights into the mechanisms underlying tumor responsiveness to pharmacological treatments.

Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors with somatostatin analogues.

BACKGROUND: Clinical experience with the radiolabeled somatostatin analogues 90Y-DOTATOC and, more recently, 177Lu-DOTATATE, is ongoing since more than a decade in few centers. Dosimetric studies demonstrated that 90Y-DOTATOC and 177Lu-DOTATATE are able to deliver high doses to somatostatin receptor sst2-expressing tumors and low doses to normal organs. RESULTS AND CONCLUSIONS: Clinical studies demonstrated that partial and complete objective responses in up to 30% of patients can be obtained, with a great survival benefit in treated patients. Side effects may involve the kidney and the bone marrow and are usually mild. Renal protection is used to minimize the risk of a late decrease of renal function.

Percutaneous cholecystostomy in the treatment of acute cholecystitis: is there still a role? A 20-year literature review.

OBJECTIVE: Percutaneous cholecystostomy (PC) is used for the treatment of acute cholecystitis in patients with high surgical risk due to the severity of cholecystitis and/or the underlying acute or chronic medical comorbidities. The evidence for this strategy is unclear. MATERIALS AND METHODS: We searched PubMed and the Cochrane databases for English-language studies published from January 1979 through December 31, 2019, for randomized clinical trials (RCTs), meta-analyses, systematic reviews, and observational studies. RESULTS: The two randomized studies that have compared PC with cholecystectomy (CCY) or conservative treatment have shown that the clinical outcomes did not differ significantly between the groups. Similar results have been found in the large majority of retrospective cohorts or single-center studies that have compared PC with CCY. CONCLUSIONS: PC does not seem to offer any benefit compared with CCY in the treatment of acute cholecystitis in patients with high surgical risk due to the severity of cholecystitis and/or the underlying acute or chronic medical comorbidities. A large, prospective, randomized study that compares percutaneous PC and CCY in patients with high surgical risk and/or moderate to severe cholecystitis is warranted.

[Vitamin D deficiency and osteoporosis in a rural population of Cordoba province, Argentina]. / Déficit de vitamina D y osteoporosis en una población rural de montaña en Córdoba, Argentina.

INTRODUCTION: Vitamin D deficiency is defined when blood levels of 25-hydroxyvitamin D (25 (OH) D) is less than ng / mmol/L. The status of Vitamin D level is associated with clinical, pathological and physiological changes as increased of parathyroid hormone, bone remodeling, osteoporosis and increased risk of fractures. Moreover,vitamin D and its metabolites are known to be associated with multiple chronic diseases as diabetes mellitus, autoimmune, cardiovascular and neoplasia diseases. OBJECTIVE: To assess the vitamin D status in a rural population of Córdoba Province in Argentina and its relation with bone mineral density. MATERIAL AND METHODS: We prospectively studied 31 patients over 50 years old who live in a rural population of Pampa de Achala in Córdoba Province, Argentina. This city is located in Córdoba High mountains. Blood vitamin D levels were tested in 24 patients and Bone mineral density in 31 patients. Vitamin D level was determined by HPLC. The vitamin D level were considered normal between 20-50 ng/ml in the winter season and 20-80 ng/ml in the summer season. Bone mineral density of lumbar spine and femoral neck was measured by DXA GE LUNAR DPX-L, according to World Health organization classification (37). The data were analyzed by Spearman coefficient and Chi cuadrado. RESULTS: The vitamin D levels samples were available in 24 patients. Mean blood Vitamin D level was 24.54 ng /ml. 8 of them (33%) had vitamin D level less than 20ng/ ml. 83% (20) of the analysed patients had vitamin D level less than 30 ng/ml and only 4 patients has vitamin D level more than 30 ng/ml. Low bone mineral density of lumbar spine and femoral neck was found in 66 % of the patients. 19 % of the patients were diagnosed of lumbar spine and femoral neck osteoporosis and 29 % of them had lumbar spine meanwhile 25 % had femoral neck. There was not statistically significant association between vitamin D level and bone mineral density analysed by Chi Cuadrado (p<0.07). A significant association was found between blood vitamin D level and low bone mineral density of femoral neck (Spearman 0.51) CONCLUSIONS: Vitamin D insufficiency is high in the rural adult population of Pampa de Achala in Córdoba and it could be a major health problem in this population.

Author Correction: Superconductor to resistive state switching by multiple fluctuation events in NbTiN nanostrips.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Superconductor to resistive state switching by multiple fluctuation events in NbTiN nanostrips.

We report on measurements of the switching current distributions on two-dimensional superconducting NbTiN strips that are 5 nm thick and 80 nm wide. We observe that the width of the switching current distributions has a non-monotonous temperature dependence, where it is constant at the lowest temperatures up to about 1.5 K, after which it increases with temperature until 2.2 K. Above 2.5 K any increase in temperature decreases the distribution width which at 4.0 K is smaller than half the width observed at 0.3 K. By using a careful analysis of the higher order moments of the switching distribution, we show that this temperature dependence is caused by switching due to multiple fluctuations. We also find that the onset of switching by multiple events causes the current dependence of the switching rate to develop a characteristic deviation from a pure exponential increase, that becomes more pronounced at higher temperatures, due to the inclusion of higher order terms.

Actions of placental and fetal adrenal steroid hormones in primate pregnancy.

It is clear that steroid hormones of placental and fetal adrenal origin have critically important roles in regulating key physiological events essential to the maintenance of pregnancy and development of the fetus for extrauterine life. Thus, progesterone has suppressive actions on lymphocyte proliferation and activity and on the immune system to prevent rejection of the developing fetus and placenta (see Fig. 9). Progesterone also suppresses the calcium-calmodulin-MLCK system and thus activity of uterine smooth muscle, thereby promoting myometrial quiescence to ensure the maintenance of pregnancy. Estrogen enhances uteroplacental blood flow and possibly placental neovascularization to provide optimal gas exchange and the nutrients required for the rapidly developing fetus and placenta. In turn, estrogen has specific stimulatory effects on the receptor-mediated uptake of LDL by, and P-450scc activity within, syncytiotrophoblasts, thus promoting the biosynthesis of progesterone. Moreover, there is an estrogen-dependent developmental regulation of expression of the LDL receptor and NAD-dependent 11 beta-HSD in the placenta, processes reflecting functional/biochemical differentiation of the trophoblast cells with advancing gestation. The increase in 11 beta-HSD causes a change in transplacental corticosteroid metabolism, which results in activation of the HPAA in the fetus. As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, e.g. 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland. In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor. At midgestation, estrogen also selectively feeds back on the fetal adrenal to suppress DHA and maintain physiologically normal levels of estrogen. Preparation of the breast for lactation and nourishment of the newborn appears to involve a multifactorial system of regulation that includes estrogen. It is apparent, therefore, that autocrine/paracrine, as well as endocrine, systems of regulation are operative within the fetoplacental unit during primate pregnancy. A major goal of this review has been to illustrate the critically close functional communication existing between the developing placenta and fetus in the biosynthesis and the actions of steroid hormones during primate pregnancy. The functional interaction of the human fetal adrenal and placenta with respect to the biosynthesis of estrogen was demonstrated many years ago. However, the recent studies presented in this review show that the endocrine interaction between the fetus and placenta is more extensive, involving complex physiological regulatory mechanisms. Thus, as illustrated in Fig. 9, estrogen, acting via its receptor within the placenta and other reproductive tissues, orchestrates the dynamic interchange between the placenta and fetus responsible for the developmental regulation of the biosynthesis of the various steroid and peptide hormones and their receptors necessary for the maintenance of pregnancy and development of a live newborn. It would appear, therefore, that the immediate and long range challenges in this area of reproductive endocrinology are to employ in vitro molecular and in vivo experimental approaches simultaneously to elucidate the nature of these complex interactions and define the cellular and molecular mechanisms underlying these important regulatory events.

Placental steroid hormone biosynthesis in primate pregnancy.

Substantial advances in our understanding of placental function have resulted from recent establishment of in vitro approaches, such as cell culture, and application of molecular methods to study placental steroidogenesis. Insight into the processes of placental cell differentiation and hormonal function has been gained from culture of relatively pure preparations of cytotrophoblast. Various factors, e.g. cAMP and peptide growth factors, have been shown to have striking effects on progesterone and estrogen formation by placental tissue under in vitro conditions. Using advanced molecular approaches, the genes governing specific enzymes critical to placental steroidogenesis have been identified. Regulation of the mRNAs encoding specific enzyme peptides and thus expression of the genes by factors, such as cAMP, have been elucidated by Northern analysis and other techniques. It is critical that these contemporary approaches continue to be implemented aggressively to further elucidate placental function. However, it is clear from a survey of the literature, particularly of the past decade, that the vast majority of investigation in the area has been conducted in vitro. It is essential to determine whether the factors that have been observed to regulate placental endocrine function in vitro are operable in vivo. It is only with in vivo study that the dynamics of steroidogenesis and the complex functional relationships between placenta, fetus, and mother will be uncovered and understood. It is increasingly evident that the regulation of placental steroidogenesis involves autocrine and/or paracrine mechanisms, similar to those integral to hormone biosynthesis within other reproductive organs, e.g. ovary and testis. For example, as discussed above, estrogen regulates LDL uptake and P-450scc, and thus apparently is involved in generating substrate for progesterone production within the placenta. Conversely, progesterone has effects on 17 beta-hydroxysteroid oxidoreductase and thus the metabolism of estradiol, while androgens exert marked inhibitory effects on placental progesterone formation, at least in vitro. Not surprisingly, the regulation of placental progesterone and estrogen formation also is multifactorial. Thus, aromatase activity is stimulated synergistically by cAMP and phorbol esters, an effect that is suppressed by peptide growth factors. Therefore, the autocrine/paracrine and multifactorial regulation of hormone biosynthesis that has been relatively well documented in other tissues should be recognized as important in the primate placenta. Finally, the basic mechanisms underlying regulation of steroidogenesis within the fetoplacental unit during primate pregnancy appear similar, in important ways, to those of widely used laboratory animals, such as the rat and rabbit.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of the primate fetal adrenal cortex.

Significant advances in our understanding of the regulation of fetal adrenal growth, differentiation, and steroidogenesis have been made in the past several years. In vitro studies employing molecular biological techniques have demonstrated that the placenta and several fetal tissues synthesize growth factors and/or oncogene-related products, which have the capacity to modulate growth and maturation of the fetal adrenal. Moreover, there is evidence that the fetal adrenal itself produces IGF-I and IGF-II and that the mRNAs for these growth factors are responsive to ACTH and perhaps other peptides originating in the fetal pituitary and/or the placenta. Most fascinating are the studies demonstrating that growth factors may also regulate the pattern of steroidogenesis elicited by the fetal adrenal. For example, TGF beta modulates binding, internalization, and degradation of LDL-cholesterol in adult adrenals while IGF-I increases fetal adrenal steroidogenesis by mechanisms that do not involve induction of P-450scc or enhanced metabolism of LDL. These studies, coupled with the observation that activation of protein kinase C by EGF or bFGF can block ACTH and/or other cAMP-induced increases in the activity of P-450(17 alpha), provide new insight into the subcellular mechanisms that underlie the regulation of fetal adrenal function. However, in vivo investigations must be aggressively pursued because the latter provide a major and perhaps exclusive means to elucidate the complex and multiple mechanisms that are apparently operative in utero in the regulation of fetal adrenal development. Moreover, in vivo studies remain the only valid means to delineate whether the factors that have been shown to modulate fetal adrenal function in vitro are indeed operable in vivo. Thus, in vivo investigations have shown that a multifactorial regulation of the fetal adrenal exists in utero in which PRL and perhaps other peptides as well as ACTH selectively stimulate fetal adrenal androgen production. Moreover, in vivo studies have demonstrated that a feedback mechanism operates in utero whereby estrogen produced in the placenta from androgen precursors of fetal adrenal origin feeds back to modulate the responsivity of the fetal adrenal to tropic peptides perhaps by regulating peptide binding to cell membrane receptors and/or other mechanisms. Evidence has also been provided from in vivo studies to support the concept that the placenta via metabolism of maternal cortisol and cortisone regulates fetal pituitary production of ACTH by modulating the extent to which maternal cortisol arrives at the fetus.(ABSTRACT TRUNCATED AT 400 WORDS)