Trimester-specific reference intervals for thyroid function parameters in pregnant Caucasian women using Roche platforms: a prospective study.

BACKGROUND: Standard thyroid function parameters reference intervals (RI) are unsuitable during pregnancy, potentially resulting in incongruous treatments that may cause adverse effects on pregnancy outcomes. We aimed at defining trimester-specific TSH, FT4 and FT3 RI, using samples longitudinally collected from healthy Caucasian women. MATERIALS AND METHODS: Blood samples from 150 healthy Caucasian women, who had a physiological gestation and a healthy newborn at term, were collected in each trimester and at around six months post-partum. They showed mild iodine deficiency. After excluding women with overt TSH abnormalities (> 10 mU/L) and/or TPO antibodies, data from 139 pregnant women were analyzed by means of widely used Roche platforms, and TSH, FT4 and FT3 trimester-specific RI were calculated. Post-partum data were available for 55 subjects. RESULTS: Serum TSH RI were 0.34-3.81 mU/L in the first trimester, and changed slightly to 0.68-4.07 U/L and 0.63-4.00 mU/L in the second and third trimester, respectively. Conversely, both FT4 and FT3 concentrations progressively decreased during pregnancy, the median values in the third trimester being 14.8% and 13.2% lower, respectively, than in the first trimester. Thyroid function parameters in the first trimester were similar to those measured after the end of pregnancy. CONCLUSIONS: This study calculates trimester-specific RI for thyroid function parameters in pregnancy, and proposes the reference limits that should be adopted when using Roche platforms in Caucasian women.

The physiological sonographic features of the ovary in healthy subjects: a joint systematic review and meta-analysis by the Italian Society of Gynecology and Obstetrics (SIGO) and the Italian Society of Endocrinology (SIE).

PURPOSE: There is a lack of uniformity in the definition of normal ovary ultrasound parameters. Our aim was to summarize and meta-analyze the evidence on the topic. Full-text English articles published through December 31, 2020 were retrieved via MEDLINE and Embase. Data available for meta-analysis included: ovarian follicular count, ovarian volume, and ovarian Pulsatility Index (PI) assessed by Doppler ultrasound. METHODS: Cohort, cross-sectional, prospective studies with a single or double arm were considered eligible. Interventional studies were included when providing baseline data. Both studies on pre- and post-menopausal women were screened; however, data on menopausal women were not sufficient to perform a meta-analysis. Studies on pre-pubertal girls were considered separately. Eighty-one papers were included in the meta-analysis. RESULTS: The mean ovarian volume was 6.11 [5.81-6.42] ml in healthy women in reproductive age (5.81-6.42) and 1.67 ml [1.02-2.32] in pre-pubertal girls. In reproductive age, the mean follicular count was 8.04 [7.26-8.82] when calculated in the whole ovary and 5.88 [5.20-6.56] in an ovarian section, and the mean ovarian PI was 1.86 [1.35-2.37]. Age and the frequency of the transducers partly modulated these values. In particular, the 25-30-year group showed the higher mean follicular count (9.27 [7.71-10.82]), followed by a progressive age-related reduction (5.67 [2.23-9.12] in fertile women > 35 years). A significant difference in follicular count was also found according to the transducer's upper MHz limit. CONCLUSION: Our findings provide a significant input to improve the interpretation and diagnostic accuracy of ovarian ultrasound parameters in different physiological and pathological settings.

Large coefficient of variation of inter-spike intervals induced by noise current in the resonate-and-fire model neuron.

Neuronal spike variability is a statistical property associated with the noise environment. Considering a linearised Hodgkin-Huxley model, we investigate how large spike variability can be induced in a typical stellate cell when submitted to constant and noise current amplitudes. For low noise current, we observe only periodic firing (active) or silence activities. For intermediate noise values, in addition to only active or inactive periods, we also identify a single transition from an initial spike-train (active) to silence dynamics over time, where the spike variability is low. However, for high noise current, we find intermittent active and silence periods with different values. The spike intervals during active and silent states follow the exponential distribution, which is similar to the Poisson process. For non-maximal noise current, we observe the highest values of inter-spike variability. Our results suggest sub-threshold oscillations as a possible mechanism for the appearance of high spike variability in a single neuron due to noise currents.

Impact of endometriosis on obstetric outcome after natural conception: a multicenter Italian study.

PURPOSE: To evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy. METHODS: Cases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis. RESULTS: Three hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22-4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23-3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23-3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49-79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69-38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38-22.09). CONCLUSION: Women with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery. TRIAL REGISTRATION: Clinical trial registration number: NCT03354793.

In-vivo and in-vitro impact of high-dose rate radiotherapy using flattening-filter-free beams on the anti-tumor immune response.

INTRODUCTION: Modern accelerators have the "flattening filter-free" (FFF) technique to deliver RT with a moderate high-dose rate, currently used in limited clinical indications. No scientifically established data are currently available on the possible effects of this high dose rate on the anti-tumor immune response. We therefore propose here to study these effects in a preclinical CT26 murine colorectal tumor model. MATERIAL AND METHODS: In-vitro, CT26 cells were irradiated on a Varian TrueBeam® linac at 3 different dose rates (4; 12 or 24 Gy/min) using the FFF mode. Activation of the anti-tumor immune response was evaluated by the analysis of induction of genes of the type I interferon pathway by RT-qPCR, and by the study of the induction of immunogenic death biomarkers. In-vivo, an efficacy study of RT delivering 16.5 Gy at 2 different dose rates was performed in immunocompetent Balb/c mice carrying CT26 syngeneic tumors, as well as an immunomonitoring analysed by flow cytometry and a transcriptomic analysis using RNA sequencing. Statistical analyzes were performed using non-parametric tests. RESULTS: In-vitro, no significant influence of an increase in FFF dose rate was shown for the induction of genes of the type I interferon pathway as well as for the studied immunogenic death markers (HMGB1 secretion). In-vivo, no difference in terms of tumor growth retardation between the 2 dose rates used was demonstrated, as well as for the composition of immune cell infiltrates within tumor microenvironment and the expression of immune checkpoints in immunomonitoring and RNAseq. CONCLUSION: In this study involving the CT26 model, no influence of a moderate high dose rate in FFF technique on the anti-tumor immune response was demonstrated, which would make studies of associations between RT and checkpoint inhibitors fit with this technique of RT. However, further explorations using other cellular models seem to be of interest.

Increased grp78 transcription is correlated to reduced tlr4 transcription in patients surviving sepsis.

Regulated transcriptional readthrough during stress maintains genome structure and ensures access to genes that are necessary for cellular recovery. A broad number of genes, including of the bacterial sensor Toll-like receptor 4 (TLR-4), are markedly transcribed on initiating the systemic inflammatory response. Here we study the transcriptional patterns of tlr4 and of its modulator grp78 during human sepsis, and establish their correlations with the outcome of patients. We measured the daily tlr4 and grp78 RNA expression levels in peripheral blood of septic patients, immediately after admission to intensive care, and modeled these RNA values with a sine damping function. We obtained negative correlations between the transcription of tlr4 and grp78 RNA in the survivor group. In contrast, such relation is lost in the deceased patients. Loss of transcriptional homeostasis predicted by our model within the initial 4 days of hospitalization was confirmed by death of those patients up to 28 days later.

Endometriosis: seeking optimal management in women approaching menopause.

The incidence of endometriosis in middle-aged women is not minimal compared to that in the reproductive age group. The treatment of affected women after childbearing age to the natural transition toward menopause has received considerably poor attention. Disease management is problematic for these women due to increased contraindications regarding hormonal treatment and the possibility for malignant transformation, considering the increased cancer risk in patients with a long-standing history of the disease. This state-of-the-art review aims for the first time to assess the benefits of the available therapies to help guide treatment decisions for the care of endometriosis in women approaching menopause. Progestins are proven effective in reducing pain and should be preferred in these women. According to the international guidelines that lack precise recommendations, hysterectomy with bilateral salpingo-oophorectomy should be the definitive therapy in women who have completed their reproductive arc, if medical therapy has failed. Strict surveillance or surgery with removal of affected gonads should be considered in cases of long-standing or recurrent endometriomas, especially in the presence of modifications of ultrasonographic cyst patterns. Although rare, malignant transformation of various tissues in endometriosis patients has been described, and management is herein discussed.

Dose constraints for moderate hypofractionated radiotherapy for prostate cancer: The French genito-urinary group (GETUG) recommendations.

Considering recent phase III trials results, moderate hypofractionated radiotherapy can be considered as a standard treatment for low and intermediate risk prostate cancer management. This assessment call for a framework allowing homogeneous and reproducible practices in the different centers using this radiotherapy schedule. The French Genito-Urinary Group (GETUG) provides here recommendations for daily practice of moderate hypofractionated radiotherapy for prostate cancer, with indications, dose, fractionation, pre-treatment planning, volume of interest delineation (target volume and organs at risk) and margins, dose constraints and radiotherapy techniques.

Evidence for several dipolar quasi-invariants in liquid crystals.

The quasi-equilibrium states of an observed quantum system involve as many constants of motion as the dimension of the operator basis which spans the blocks of all the degenerate eigenvalues of the Hamiltonian that drives the system dynamics, however, the possibility of observing such quasi-invariants in solid-like spin systems in Nuclear Magnetic Resonance (NMR) is not a strictly exact prediction. The aim of this work is to provide experimental evidence of several quasi-invariants, in the proton NMR of small spin clusters, like nematic liquid crystal molecules, in which the use of thermodynamic arguments is not justified. We explore the spin states prepared with the Jeener-Broekaert pulse sequence by analyzing the time-domain signals yielded by this sequence as a function of the preparation times, in a variety of dipolar networks, solids, and liquid crystals. We observe that the signals can be explained with two dipolar quasi-invariants only within a range of short preparation times, however at longer times liquid crystal signals show an echo-like behaviour whose description requires assuming more quasi-invariants. We study the multiple quantum coherence content of such signals on a basis orthogonal to the z-basis and see that such states involve a significant number of correlated spins. Therefore, we show that the NMR signals within the whole preparation time-scale can only be reconstructed by assuming the occurrence of multiple quasi-invariants which we experimentally isolate.

Low body weight and menstrual dysfunction are common findings in both elite and amateur ballet dancers.

BACKGROUND: Several studies have reported that low body weight and menstrual alterations are very frequent findings in elite dancers, suggesting they could be at risk for associated medical problems. However, it is still largely unknown whether these alterations are also common in the very large number of young amateur dancers. AIM: The aim of this study was to assess whether there is an increased prevalence of menstrual dysfunction also in amateur dancers. MATERIAL/SUBJECTS AND METHODS: Ninety-two professional ballet dancers, 93 non-professional ballet dancers, and 293 (160 sedentary, 133 physically active) control women, ranging in age 14-23 yr, were included in the study. In these subjects, a detailed questionnaire that included questions on weight, height, age at menarche, training profile and menstrual alterations was administered. RESULTS: BMI was lower in both professional and non-professional dancers than in controls. Frequency of menstrual dysfunction was 51%, 34% and 21% in professional dancers, non-professional dancers and controls, respectively (p<0.0001). Amenorrhea was reported by 23% of professional dancers, vs 1-7% in the other groups (p<0.0001). Age at menarche occurred later in professional dancers than in the other groups. Logistic regression analyses showed that menstrual dysfunction was associated with the training profile in professional dancers, and with BMI in non-professional dancers. Age at menarche was associated with menstrual dysfunction in both groups. CONCLUSIONS: This study shows that low body weight and menstrual dysfunction are frequent findings also in amateur ballet dancers.

Severe and refractory myositis in mixed connective tissue disease: a description of a rare case.

Mixed connective tissue disease (MCTD) is a rare disease that includes clinical and laboratorial manifestations of systemic lupus erythematosus, scleroderma and polymyositis that is associated with high titers of anti-U1RNP antibodies. In general, muscle involvement is subclinical, usually appearing as an increase in muscle enzyme levels that tends to be a characteristic of the initial phases of the disease. Severe clinical muscle weakness is not observed in this disease. The objective of this study is to report a rare case of a patient who presented a severe onset of myositis characterized by dysphagia, an increase in myopathy and a weakening of the cervical musculature. While there was no response to the administration of an initial dose of corticosteroids, improvement was observed after increasing the dose of corticosteroids, in addition to the initiation of pulse therapy with methylprednisolone accompanied by methotrexate treatment. The authors emphasize that there is only one previously reported case regarding a child with MCTD and severe clinical myopathy on electromyography and muscle biopsy, and they report in this article one adult female patient who presented severe myositis and was refractive to corticotherapy.

Lower serum IgA levels in horses kept under intensive sanitary management and physical training.

Quantity and variety of environmental antigens, age, diet, vaccine protocols, exercising practice and mucosal cytokine microenvironment are factors that influence serum immunoglobulin (Ig) levels. IgA, IgG, IgG(T) and IgM were quantified in 60 horses, which were classified into two groups, 'intensive' or 'relaxed', according to sanitary standards of the facilities and physical exercise to which animals were subjected to. The 'intensive' group presented lower means for all isotypes, but only IgA presented a significant (P < 0.0064) difference when compared to the 'relaxed' group. This suggests that mucosal immunity found in the 'intensive' group is lower when compared to the 'relaxed' group. Our data suggest that athlete horses may be less poised to mount an effective mucosal immunity response to environmental challenges and should not be considered by the same perspectives as a free-ranging horse.

NMR dipolar constants of motion in liquid crystals: Jeener-Broekaert, double quantum coherence experiments and numerical calculation on a 10-spin cluster.

Two proton quasi-equilibrium states were previously observed in nematic liquid crystals, namely the S and W quasi-invariants. Even though the experimental evidence suggested that they originate in a partition of the spin dipolar energy into a strong and a weak part, respectively, from a theoretical viewpoint, the existence of an appropriate energy scale which allows such energy separation remains to be confirmed and a representation of the quasi-invariants is still to be given. We compare the dipolar NMR signals yielded both by the Jeener-Broekaert (JB) experiment as a function of the preparation time and the free evolution of the double quantum coherence (DQC) spectra excited from the S state, with numerical calculations carried out from first principles under different models for the dipolar quasi-invariants, in a 10-spin cluster which represents the 5CB (4(')-pentyl-4-biphenyl-carbonitrile) molecule. The calculated signals qualitatively agree with the experiments and the DQC spectra as a function of the single-quantum detection time are sensible enough to the different models to allow both to probe the physical nature of the initial dipolar-ordered state and to assign a subset of dipolar interactions to each constant of motion, which are compatible with the experiments. As a criterion for selecting a suitable quasi-equilibrium model of the 5CB molecule, we impose on the time evolution operator consistency with the occurrence of two dipolar quasi-invariants, that is, the calculated spectra must be unaffected by truncation of non-secular terms of the weaker dipolar energy. We find that defining the S quasi-invariant as the subset of the dipolar interactions of each proton with its two nearest neighbours yields a realistic characterization of the dipolar constants of motion in 5CB. We conclude that the proton-spin system of the 5CB molecule admits a partition of the dipolar energy into a bilinear strong and a multiple-spin weak contributions therefore providing two orthogonal constants of motion, which can be prepared and observed by means of the JB experiment. This feature, which implies the existence of two timescales of very different nature in the proton-spin dynamics, is ultimately dictated by the topology of the spin distribution in the dipole network and can be expected in other liquid crystals. Knowledge of the nature of the dipolar quasi-invariants will be useful in studies of dipolar-order relaxation, decoherence and multiple quantum NMR experiments where the initial state is a dipolar-ordered one.

Quasiequilibrium states in thermotropic liquid crystals studied by multiple-quantum NMR.

Previous work showed that by means of the Jeener-Broekaert (JB) experiment, two quasiequilibrium states can be selectively prepared in the proton spin system of thermotropic nematic liquid crystals (LCs) in a strong magnetic field. The similarity of the experimental results obtained in a variety of LC in a broad Larmor frequency range, with crystal hydrates, supports the assumption that also in LC the two spin reservoirs, into which the Zeeman order is transferred, originate in the dipolar energy and that they are associated with a separation in energy scales: A constant of motion related to the stronger dipolar interactions (S), and a second one (W) corresponding to the secular part of the weaker dipolar interactions with regard to the Zeeman and the strong dipolar part. We study the nature of these quasi-invariants in nematic 5CB (4(')-pentyl-4-biphenyl-carbonitrile) and measure their relaxation times by encoding the multiple-quantum coherences of the states following the JB pulse pair on two orthogonal bases, Z and X. The experiments were also performed in powder adamantane at 301 K which is used as a reference compound having only one dipolar quasi-invariant. We show that the evolution of the quantum states during the buildup of the quasiequilibrium state in 5CB prepared under the S condition is similar to the case of powder adamantane and that their quasiequilibrium density operators have the same tensor structure. In contrast, the second constant of motion, whose explicit operator form is not known, involves a richer composition of multiple-quantum coherences of even order on the X basis, in consistency with the truncation inherent in its definition. We exploited the exclusive presence of coherences of +/-4,+/-6,+/-8, besides 0 and +/-2 under the W condition to measure the spin-lattice relaxation time T(W) accurately, so avoiding experimental difficulties that usually impair dipolar order relaxation measurement such as Zeeman contamination at high fields and also superposition of the different quasi-invariants. This procedure opens the possibility of measuring the spin-lattice relaxation of a quasi-invariant independent of the Zeeman and S reservoirs, so incorporating a new relaxation parameter useful for studying the complex molecular dynamics in mesophases. In fact, we report the first measurement of T(W) in a LC at high magnetic fields. Comparison of the obtained value with the one corresponding to a lower field (16 MHz) points out that the relaxation of the W-order strongly depends on the intensity of the external magnetic field, similarly to the case of the S reservoir, indicating that the relaxation of the W-quasi-invariant is also governed by the cooperative molecular motions.

[Prevalence of diabetes treated with drugs in Andalucía. Evolution of the oral antidiabetics and insulin prescription between 1994 and 2000]. / Prevalencia de diabetes tratada con fármacos en Andalucía. Evolución de la prescripción de antidiabéticos orales e insulina entre 1994 y 2000.

CONTEXT: [corrected] Diabetes is an important, complex, expensive, and increasingly frequent disease. The objective of this study was to investigate the diabetes mellitus prevalence and evolution in the Adalusian population between 1994 and 2000. METHODS: We used and indirect method for estimating the rate of prevalence of the disease based on antidiabetic drug consumption data at regional level, using the official billing data, and the annual population data. RESULTS: The prevalence estimated for diabetes mellitus in Andalusia was, 4.41%. This prevalence ranged from 2.47% in 1994 up to 4.41% in 2000. Oral antidiabetics/insulin use ratio was 2.31. The study shows an important variability of the prescription habits in diabetic patients in Andalucía. CONCLUSIONS: The prevalence observed in diabetes mellitus in Andalucía increased between 1994 and 2000. An important variability was observed among the different provinces.

A bifunctional epimerase-reductase acts downstream of the MUR1 gene product and completes the de novo synthesis of GDP-L-fucose in Arabidopsis.

L-Fucose is a monosaccharide found as a component of glycoproteins and cell wall polysaccharides in higher plants. The MUR1 gene of Arabidopsis thaliana encodes a GDP-D-mannose 4,6-dehydratase catalyzing the first step in the de novo synthesis of GDP-L-fucose from GDP-D-mannose (Bonin et al. 1997, Proc. Natl Acad. Sci. USA, 94, 2085-2090). Plant genes encoding the subsequent steps in L-fucose synthesis (3,5-epimerization and 4-reduction) have not been described previously. Based on sequence similarities to a bacterial gene involved in capsule synthesis we have cloned a gene from Arabidopsis, now designated GER1, which encodes a bifunctional 3, 5-epimerase-4-reductase in L-fucose synthesis. The combined action of the MUR1 and GER1 gene products converts GDP-D-mannose to GDP-L-fucose in vitro demonstrating that this entire nucleotide-sugar interconversion pathway could be reconstituted using plant genes expressed in Escherichia coli. In vitro assays indicated that the GER1 protein does not act as a GDP-D-mannose 3, 5-epimerase, an enzymatic activity involved in the de novo synthesis of GDP-L-galactose and L-ascorbic acid. Similarly, L-ascorbate levels in GER1 antisense plants were unchanged indicating that GDP-D-mannose 3,5-epimerase is encoded by a separate gene.

The MUR1 gene of Arabidopsis thaliana encodes an isoform of GDP-D-mannose-4,6-dehydratase, catalyzing the first step in the de novo synthesis of GDP-L-fucose.

GDP-L-fucose is the activated nucleotide sugar form of L-fucose, which is a constituent of many structural polysaccharides and glycoproteins in various organisms. The de novo synthesis of GDP-L-fucose from GDP-D-mannose encompasses three catalytic steps, a 4,6-dehydration, a 3,5-epimerization, and a 4-reduction. The mur1 mutant of Arabidopsis is deficient in L-fucose in the shoot and is rescued by growth in the presence of exogenously supplied L-fucose. Biochemical assays of the de novo pathway for the synthesis of GDP-L-fucose indicated that mur1 was blocked in the first nucleotide sugar interconversion step, a GDP-D-mannose-4,6-dehydratase. An expressed sequence tag was identified that showed significant sequence similarity to proposed bacterial GDP-D-mannose-4,6-dehydratases and was tightly linked to the mur1 locus. A full-length clone was isolated from a cDNA library, and its coding region was expressed in Escherichia coli. The recombinant protein exhibited GDP-D-mannose-4,6-dehydratase activity in vitro and was able to complement mur1 extracts in vitro to complete the pathway for the synthesis of GDP-L-fucose. All seven mur1 alleles investigated showed single point mutations in the coding region for the 4,6-dehydratase, confirming that it represents the MUR1 gene.