Evidence of brain injury in fetuses of mothers with preterm labor with intact membranes and preterm premature rupture of membranes.

BACKGROUND: Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers. OBJECTIVE: This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator. STUDY DESIGN: In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission. RESULTS: Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002). CONCLUSION: Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.

Lung Inflammatory Phenotype in Mice Deficient in Fibulin-2 and ADAMTS-12.

Interaction between extracellular matrix (ECM) components plays an important role in the regulation of cellular behavior and hence in tissue function. Consequently, characterization of new interactions within ECM opens the possibility of studying not only the functional but also the pathological consequences derived from those interactions. We have previously described the interaction between fibulin2 and ADAMTS-12 in vitro and the effects of that interaction using cellular models of cancer. Now, we generate a mouse deficient in both ECM components and evaluate functional consequences of their absence using different cancer and inflammation murine models. The main findings indicate that mice deficient in both fibulin2 and ADAMTS12 markedly increase the development of lung tumors following intraperitoneal urethane injections. Moreover, inflammatory phenotype is exacerbated in the lung after LPS treatment as can be inferred from the accumulation of active immune cells in lung parenchyma. Overall, our results suggest that protective effects in cancer or inflammation shown by fibulin2 and ADAMTS12 as interactive partners in vitro are also shown in a more realistic in vivo context.

Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.

BACKGROUND: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. OBJECTIVE: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. STUDY DESIGN: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. RESULTS: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. CONCLUSION: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.

Immunolocalization of the mechanogated ion channels PIEZO1 and PIEZO2 in human and mouse dental pulp and periodontal ligament.

PIEZO1 and PIEZO2 are essential components of mechanogated ion channels, which are required for mechanotransduction and biological processes associated with mechanical stimuli. There is evidence for the presence of PIEZO1 and PIEZO2 in teeth and periodontal ligaments, especially in cell lines and mice, but human studies are almost nonexistent. Decalcified permanent human teeth and mouse molars were processed for immunohistochemical detection of PIEZO1 and PIEZO2. Confocal laser microscopy was used to examine the co-localization of PIEZO 1 and PIEZO2 with vimentin (a marker of differentiated odontoblasts) in human teeth. In the outer layer of the human dental pulp, abundant PIEZO1- and PIEZO2-positive cells were found that had no odontoblast morphology and were vimentin-negative. Based on their morphology, location, and the absence of vimentin positivity, they were identified as dental pulp stem cells or pre-odontoblasts. However, in mice, PIEZO1 and PIEZO2 were ubiquitously detected and colocalized in odontoblasts. Intense immunoreactivity of PIEZO1 and PIEZO2 has been observed in human and murine periodontal ligaments. Our findings suggest that PIEZO1 and PIEZO2 may be mechanosensors/mechanotransducers in murine odontoblasts, as well as in the transmission of forces by the periodontal ligament in humans and mice.

A multivariable prediction model for intra-amniotic infection in patients with preterm labor and intact membranes including a point of care system that measures amniotic fluid MMP-8.

OBJECTIVES: Among patients with preterm labor and intact membranes (PTL), those with intra-amniotic infection (IAI) present the highest risk of adverse perinatal outcomes. Current identification of IAI, based on microbiological cultures and/or polymerase chain reaction amplification of the 16S ribosomal RNA gene, delay diagnosis and, consequently, antenatal management. The aim to of the study was to assess the performance of a multivariable prediction model for diagnosing IAI in patients with PTL below 34.0 weeks using clinical, sonographic and biochemical biomarkers. METHODS: From 2019 to 2022, we prospectively included pregnant patients admitted below 34.0 weeks with diagnosis of PTL and had undergone amniocentesis to rule in/out IAI. The main outcome was IAI, defined by a positive culture and/or 16S ribosomal RNA gene in amniotic fluid. Based on the date of admission, the sample (n=98) was divided into a derivation (2019-2020, n=49) and validation cohort (2021-2022, n=49). Logistic regression models were developed for the outcomes evaluated. As predictive variables we explored ultrasound cervical length measurement at admission, maternal C-reactive protein, gestational age, and amniotic fluid glucose and matrix metalloproteinase-8 (MMP-8) levels. The model was developed in the derivation cohort and applied to the validation cohort and diagnostic performance was evaluated. Clinical management was blinded to the model results. RESULTS: During the study period, we included 98 patients admitted with a diagnosis of PTL. Of these, 10 % had IAI. The final model included MMP-8 and amniotic fluid glucose levels and showed an area under the receiver operating characteristic curve to predict the risk of IAI of 0.961 (95 % confidence interval: 0.860-0.995) with a sensitivity of 75 %, specificity of 93.3 %, positive likelihood ratio (LR) of 11.3 and negative LR of 0.27 in the validation cohort. CONCLUSIONS: In patients with PTL, a multivariable prediction model including amniotic fluid MMP-8 and glucose levels might help in the clinical management of patients undergoing amniocentesis to rule in/out IAI, providing results within a few minutes.

Immunohistochemical detection of PIEZO1 and PIEZO2 in human digital Meissner´s corpuscles.

BACKGROUND: The cutaneous end organ complexes or cutaneous sensory corpuscles are specialized sensory organs associated to low-threshold mechanoreceptors. Mechano-gated proteins forming a part of ion channels have been detected in both the axon and terminal glial cells of Meissner corpuscles, a specific cutaneous end organ complex in the human glabrous skin. The main candidates to mechanotransduction in Meissner corpuscles are members of the Piezo family of cationic ion channels. PIEZO2 has been detected in the axon of these sensory structures whereas no data exists about the occurrence and cell localization of PIEZO1. METHODS: Skin samples (n = 18) from the palmar aspect of the distal phalanx of the first and second fingers were analysed (8 female and 10 males; age range 26 to 61 26-61 years). Double immunofluorescence for PIEZO1 and PIEZO2 together with axonal or terminal glial cell markers was captured by laser confocal microscopy, and the percentage of PIEZOs positive Meissner corpuscles was evaluated. RESULTS: MCs from human fingers showed variable morphology and degree of lobulation. Regarding the basic immunohistochemical profile, in all cases the axons were immunoreactive for neurofilament proteins, neuron specific enolase and synaptophysin, while the lamellar cells displayed strong S100P immunoreactivity. PIEZO1 was detected co-localizing with axonal markers, but never with terminal glial cell markers, in the 56% of Meissner corpuscles; weak but specific immunofluorescence was additionally detected in the epidermis, especially in basal keratinocytes. Similarly, PIEZO2 immunoreactivity was found restricted to the axon in the 85% of Meissner corpuscles. PIEZO2 positive Merkel cells were also regularly found. CONCLUSIONS: PIEZO1 and PIEZO2 are expressed exclusively in the axon of a subpopulation of human digital Meissner corpuscles, thus suggesting that not only PIEZO2, but also PIEZO1 may be involved in the mechanotransduction from low-threshold mechanoreceptors.

Relationship of PIEZO1 and PIEZO2 vascular expression with diabetic neuropathy.

Introduction: Diabetic distal symmetric polyneuropathy (DDSP) is the most prevalent form of diabetic peripheral neuropathy, and 25% of patients develop pain in their toes. DDSP is associated with increased cutaneous microvessel density (MVD), reduced skin blood flow, endothelial dysfunction, and impaired fluid filtration with vasodilation. The Piezo family of mechanosensitive channels is known to be involved in the control of vascular caliber by converting mechanical force into intracellular signals. Furthermore, Piezo2 is particularly involved in peripheral pain mechanisms of DDSP patients. To date, very little is known about the number, structure, and PIEZO expression in cutaneous blood vessels (BVs) of individuals with DDSP and their relation with pain and time span of diabetes. Methods and results: We studied microvessels using endothelial markers (CD34 and CD31) and smooth cell marker (α-SMA) by indirect immunohistochemical assay in sections of the glabrous skin of the toes from patients and controls. MVD was assessed through CD34 and CD31 immunoreaction. MVD determined by CD34 is higher in short-term DDSP patients (less than 15 years of evolution), regardless of pain. However, long-term DDSP patients only had increased BV density in the painful group for CD31. BVs of patients with DDSP showed structural disorganization and loss of shape. The BVs affected by painful DDSP underwent the most dramatic structural changes, showing rupture, leakage, and abundance of material that occluded the BV lumen. Moreover, BVs of DDSP patients displayed a Piezo1 slight immunoreaction, whereas painful DDSP patients showed an increase in Piezo2 immunoreaction. Discussion: These results suggest that alterations in the number, structure, and immunohistochemical profile of specific BVs can explain the vascular impairment associated with painful DDSP, as well as the temporal span of diabetes. Finally, this study points out a possible correlation between increased vascular Piezo2 immunostaining and pain and decreased vascular Piezo1 immunostaining and the development of vasodilation deficiency.

Acid-Sensing Ion Channels' Immunoreactivity in Nerve Profiles and Glomus Cells of the Human Carotid Body.

The carotid body is a major peripheral chemoreceptor that senses changes in arterial blood oxygen, carbon dioxide, and pH, which is important for the regulation of breathing and cardiovascular function. The mechanisms by which the carotid body senses O2 and CO2 are well known; conversely, the mechanisms by which it senses pH variations are almost unknown. Here, we used immunohistochemistry to investigate how the human carotid body contributes to the detection of acidosis, analyzing whether it expresses acid-sensing ion channels (ASICs) and determining whether these channels are in the chemosensory glomic cells or in the afferent nerves. In ASIC1, ASIC2, and ASIC3, and to a much lesser extent ASIC4, immunoreactivity was detected in subpopulations of type I glomus cells, as well as in the nerves of the carotid body. In addition, immunoreactivity was found for all ASIC subunits in the neurons of the petrosal and superior cervical sympathetic ganglia, where afferent and efferent neurons are located, respectively, innervating the carotid body. This study reports for the first time the occurrence of ASIC proteins in the human carotid body, demonstrating that they are present in glomus chemosensory cells (ASIC1 < ASIC2 > ASIC3 > ASIC4) and nerves, presumably in both the afferent and efferent neurons supplying the organ. These results suggest that the detection of acidosis by the carotid body can be mediated via the ASIC ion channels present in the type I glomus cells or directly via sensory nerve fibers.

Preterm Prelabour Rupture of Membranes before Viability in Twin Pregnancies: What Can We Expect?

Preterm prelabour rupture of membranes (PPROMs) before viability carries significant perinatal mortality and morbidity. Clinical management and prenatal counselling are a challenge, especially in twin pregnancies, due to scarce evidence on how previable PPROM affects this population. The aim of this study was to describe pregnancy outcomes of twin pregnancies complicated with previable PPROM and evaluate potential prognostic factors that may predict perinatal mortality. A retrospective cohort including dichorionic and monochorionic diamniotic twin pregnancies complicated with PPROM before 24 + 0 weeks of pregnancy was evaluated. Perinatal outcomes of pregnancies managed expectantly were described. Factors predicting perinatal mortality or reaching periviability (defined from 23 + 0 weeks onwards) were evaluated. Of the 45 patients included, 7 (15.6%) spontaneously delivered within the first 24 h after diagnosis. Two patients (5.3%) requested selective termination of the affected twin. In the 36 ongoing pregnancies that opted for expectant management, the overall survival rate was 35/72 (48.6%). There were 25/36 (69.4%) patients who delivered after 23 + 0 weeks of pregnancy. When periviability was achieved, neonatal survival increased up to 35/44 (79.5%). Gestational age at delivery was the only independent risk factor of perinatal mortality. The overall survival rate of twin pregnancies complicated with previable PPROM is poor but similar to singletons. No prognostic factors, apart from achieving periviability, were identified as individual predictors of perinatal mortality.

Outpatient management of preterm prelabor rupture of membranes before 34 weeks: Maternal and neonatal outcomes.

OBJECTIVE: To evaluate the maternal, fetal, and neonatal outcomes of pregnant women complicated with preterm prelabor rupture of membranes (PPROM) eligible for outpatient care. METHODS: This study included a retrospective cohort of patients with singleton pregnancies with PPROM between 23+0 to 34+0 weeks who remained pregnant after the first 72 h. Outpatient management was considered in women with clinical, ultrasound and analytical stability, and easy access to hospital. Maternal, fetal, and neonatal results were compared between women managed as inpatients versus those managed as outpatients. RESULTS: Women eligible for the outpatient management had a better prognostic profile (no anhydramnios, longer cervical length, less intraamniotic infection, and clinical, ultrasound, and analytical stability) and presented a lower gestational age at admission and longer latency to delivery, resulting in a similar gestational age at delivery as the inpatient group. Postpartum curettage, uterine atony, respiratory distress syndrome, and bronchopulmonary dysplasia were less frequent in the outpatient group. Composite maternal-fetal morbidity and mortality outcomes were similar in both groups, while composite neonatal morbidity and mortality outcomes were significantly lower in the outpatient group. CONCLUSION: Outpatient management may be an option for women presenting stable PPROM before 34 weeks when adequate selection criteria are fulfilled. Differences in perinatal outcomes in the outpatient group compared with the inpatient group are probably attributable to baseline characteristics. Further prospective randomized studies are needed to confirm the benefits of outpatient management in PPROM.

Noninvasive prediction models of intra-amniotic infection in women with preterm labor.

BACKGROUND: Among women with preterm labor, those with intra-amniotic infection present the highest risk of early delivery and the most adverse outcomes. The identification of intra-amniotic infection requires amniocentesis, perceived as too invasive by women and physicians. Noninvasive methods for identifying intra-amniotic infection and/or early delivery are crucial to focus early efforts on high-risk preterm labor women while avoiding unnecessary interventions in low-risk preterm labor women. OBJECTIVE: This study modeled the best performing models, integrating biochemical data with clinical and ultrasound information to predict a composite outcome of intra-amniotic infection and/or spontaneous delivery within 7 days. STUDY DESIGN: From 2015 to 2020, data from a cohort of women, who underwent amniocentesis to rule in or rule out intra-amniotic infection or inflammation, admitted with a diagnosis of preterm labor at <34 weeks of gestation at the Hospital Clinic and Hospital Sant Joan de Déu, Barcelona, Spain, were used. At admission, transvaginal ultrasound was performed, and maternal blood and vaginal samples were collected. Using high-dimensional biology, vaginal proteins (using multiplex immunoassay), amino acids (using high-performance liquid chromatography), and bacteria (using 16S ribosomal RNA gene amplicon sequencing) were explored to predict the composite outcome. We selected ultrasound, maternal blood, and vaginal predictors that could be tested with rapid diagnostic techniques and developed prediction models employing machine learning that was applied in a validation cohort. RESULTS: A cohort of 288 women with preterm labor at <34 weeks of gestation, of which 103 (35%) had a composite outcome of intra-amniotic infection and/or spontaneous delivery within 7 days, were included in this study. The sample was divided into derivation (n=116) and validation (n=172) cohorts. Of note, 4 prediction models were proposed, including ultrasound transvaginal cervical length, maternal C-reactive protein, vaginal interleukin 6 (using an automated immunoanalyzer), vaginal pH (using a pH meter), vaginal lactic acid (using a reflectometer), and vaginal Lactobacillus genus (using quantitative polymerase chain reaction), with areas under the receiving operating characteristic curve ranging from 82.2% (95% confidence interval, ±3.1%) to 85.2% (95% confidence interval, ±3.1%), sensitivities ranging from 76.1% to 85.9%, and specificities ranging from 75.2% to 85.1%. CONCLUSION: The study results have provided proof of principle of how noninvasive methods suitable for point-of-care systems can select high-risk cases among women with preterm labor and might substantially aid in clinical management and outcomes while improving the use of resources and patient experience.

Localization of BDNF and Calretinin in Olfactory Epithelium and Taste Buds of Zebrafish (Danio rerio).

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and it is involved in several fundamental functions in the central and peripheral nervous systems, and in sensory organs. BDNF regulates the chemosensory systems of mammals and is consistently expressed in those organs. In zebrafish, the key role of BDNF in the biology of the hair cells of the inner ear and lateral line system has recently been demonstrated. However, only some information is available about its occurrence in the olfactory epithelium, taste buds, and cutaneous isolated chemosensory cells. Therefore, this study was undertaken to analyze the involvement of BDNF in the chemosensory organs of zebrafish during the larval and adult stages. To identify cells displaying BDNF, we compared the cellular pattern of BDNF-displaying cells with those immunoreactive for calretinin and S100 protein. Our results demonstrate the localization of BDNF in the sensory part of the olfactory epithelium, mainly in the ciliated olfactory sensory neurons in larvae and adult zebrafish. Intense immunoreaction for BDNF was also observed in the chemosensory cells of oral and cutaneous taste buds. Moreover, a subpopulation of olfactory sensory neurons and chemosensory cells of olfactory rosette and taste bud, respectively, showed marked immunopositivity for calcium-binding protein S100 and calretinin. These results demonstrate the possible role of BDNF in the development and maintenance of olfactory sensory neurons and sensory cells in the olfactory epithelium and taste organs of zebrafish during all stages of development.

Individualized treatment of preterm premature rupture of membranes to prolong the latency period, reduce the rate of preterm birth, and improve neonatal outcomes.

BACKGROUND: Preterm premature rupture of membranes complicates approximately 3% of pregnancies. Currently, in the absence of chorioamnionitis or placental abruption, expectant management, including antenatal steroids for lung maturation and prophylactic antibiotic treatment, is recommended. The benefits of individualized management have not been adequately explored. OBJECTIVE: This study aimed to compare the impact of 2 different management strategies of preterm premature rupture of membranes in 2 tertiary obstetrical centers on latency of >7 days, latency to birth, chorioamnionitis, funisitis, and short-term adverse maternal and neonatal outcomes. STUDY DESIGN: This was a multicenter retrospective study of women with singleton pregnancies with preterm premature rupture of membranes from 23 0/7 to 33 6/7 weeks of gestation between 2014 and 2018 and undelivered within 24 hours after hospital admission managed at Sunnybrook Health Sciences Center, Toronto, Canada (standard management group), and BCNatal (Hospital Clínic of Barcelona and Hospital Sant Joan de Déu Barcelona), Barcelona, Spain (individualized management group), following local protocols. The standard management group received similar management for all patients, which included a standard antibiotic regimen and routine maternal and fetal surveillance, whereas the individualized management group received personalized management on the basis of amniocentesis at hospital admission (if possible), to rule out microbial invasion of the amniotic cavity and targeted treatment. The exclusion criteria were cervical dilatation >2 cm, active labor, contraindications to expectant management (acute chorioamnionitis, placental abruption, or abnormal fetal tracing), and major fetal anomalies. The primary outcome was latency of >7 days, and the secondary outcomes included latency to birth, chorioamnionitis, and short-term adverse maternal and neonatal outcomes. Statistical comparisons between groups were conducted with propensity score weighting. RESULTS: A total of 513 pregnancies with preterm premature rupture of membranes were included in this study: 324 patients received standard management, and 189 patients received individualized management, wherein amniocentesis was performed in 112 cases (59.3%). After propensity score weighting, patients receiving individualized management had a higher latency of >7 days (76.0% vs 41.6%; P<.001) and latency to birth (18.1±14.7 vs 9.7±9.7 days; P<.001). Although a higher rate of clinical chorioamnionitis was suspected in the individualized management group than the standard group (34.5% vs 22.0%; P<.01), there was no difference between the groups in terms of histologic chorioamnionitis (67.2% vs 73.4%; P=.16), funisitis (57.6% vs 58.1%; P=.92), or composite infectious maternal outcomes (9.1% vs 7.9%; P=.64). Prolonged latency in the individualized management group was associated with a significant reduction of preterm birth at <32 weeks of gestation (72.1% vs 90.5%; P<.001), neonatal intensive care unit admission (75.6% vs 83.0%; P=.046), and neonatal respiratory support at 28 days of life (16.1% vs 26.1%; P<.01) compared with that in the standard management group. Moreover, prolonged latency was not associated with neonatal severe morbidity at discharge (survival without severe morbidity, 80.4% vs 73.5%; P=.09). CONCLUSION: Individualized management of preterm premature rupture of membranes may prolong pregnancy and reduce preterm birth at <32 weeks of gestation, the need for neonatal support, and neonatal intensive care unit admissions, without an increase in histologic chorioamnionitis, funisitis, neonatal infection-related morbidity, and short-term adverse maternal and neonatal outcomes.

The Lamellar Cells of Vertebrate Meissner and Pacinian Corpuscles: Development, Characterization, and Functions.

Sensory corpuscles, or cutaneous end-organ complexes, are complex structures localized at the periphery of Aß-axon terminals from primary sensory neurons that primarily work as low-threshold mechanoreceptors. Structurally, they consist, in addition to the axons, of non-myelinating Schwann-like cells (terminal glial cells) and endoneurial- and perineurial-related cells. The terminal glial cells are the so-called lamellar cells in Meissner and Pacinian corpuscles. Lamellar cells are variably arranged in sensory corpuscles as a "coin stack" in the Meissner corpuscles or as an "onion bulb" in the Pacinian ones. Nevertheless, the origin and protein profile of the lamellar cells in both morphotypes of sensory corpuscles is quite similar, although it differs in the expression of mechano-gated ion channels as well as in the composition of the extracellular matrix between the cells. The lamellar cells have been regarded as supportive cells playing a passive role in the process of genesis of the action potential, i.e., the mechanotransduction process. However, they express ion channels related to the mechano-electric transduction and show a synapse-like mechanism that suggest neurotransmission at the genesis of the electrical action potential. This review updates the current knowledge about the embryonic origin, development modifications, spatial arrangement, ultrastructural characteristics, and protein profile of the lamellar cells of cutaneous end-organ complexes focusing on Meissner and Pacinian morphotypes.

The BDNF/TrkB Neurotrophin System in the Sensory Organs of Zebrafish.

The brain-derived neurotrophic factor (BDNF) was discovered in the last century, and identified as a member of the neurotrophin family. BDNF shares approximately 50% of its amino acid with other neurotrophins such as NGF, NT-3 and NT-4/5, and its linear amino acid sequences in zebrafish (Danio rerio) and human are 91% identical. BDNF functions can be mediated by two categories of receptors: p75NTR and Trk. Intriguingly, BDNF receptors were highly conserved in the process of evolution, as were the other NTs' receptors. In this review, we update current knowledge about the distribution and functions of the BDNF-TrkB system in the sensory organs of zebrafish. In fish, particularly in zebrafish, the distribution and functions of BDNF and TrkB in the brain have been widely studied. Both components of the system, associated or segregated, are also present outside the central nervous system, especially in sensory organs including the inner ear, lateral line system, retina, taste buds and olfactory epithelium.

Demirjian and Cameriere methods for age estimation in a Spanish sample of 1386 living subjects.

Currently, human identification is a challenge. Migration due to war, economic crisis or other factors is frequent. The wisdom teeth are the last teeth to initiate and complete development therefore, are fundamental for determining the legal age of majority in different countries. The aim of the study is to determine the validity of two methods based on mineralisation of the third molar to predict the ages of majority of individuals in a Spanish population. Orthopantomographies of 636 men and 750 women (mean age, 16.5 years) were analysed. The Demirjian and Cameriere methods were used, and each tooth was assigned a value according to the degree of mineralisation and maturation. The level of significance used in the analyses was 5% (α = 0.05), with a power of 96.2%. The predictive ability of the Demirjian method to determine 18 years of age in the lower wisdom teeth 93%, respectively. The Cameriere method has a predictive capacity of 88%. There are no statistically significant differences between men and women. Stage H and a cut-off point of 0.08 were the guiding values for determining the age of majority of the study population. For other proposed age ranges (14 and 16 years), both methods were useful in determining the actual age of individuals, with the Demirjian method having a sensitivity of 97.5% with and Cameriere having a predictive capacity of 95%. Both methods can be used with high reliability to determine the age of individuals where reliable documentation is unavailable. Stage H with the Demirjian method and a cut-off point of 0.08 with the Cameriere method can determine the age of majority of the Spanish population. The combination of the two methods does not substantially increase predictive ability.

Factors related to inhibition of lactation by pharmacological means at birth in a Spanish referral hospital (2011-2017).

OBJECTIVE: To describe the maternal, neonatal and pregnancy characteristics related to inhibition of lactation (IL) with cabergoline. METHOD: We assessed 20,965 occasions of breastfeeding initiation, according to data collected from obstetric records at the Hospital Clinic of Barcelona (Spain) between January 2011 and December 2017. RESULTS: IL decreased over the study period from 8.78% to 6.18% (odds ratio [OR]: 0.93 per year; 95% confidence interval [95%CI]: 0.90-0.95). Women with a lower educational level (OR: 2.5; 95%CI: 2.0-3.0), mothers living in more depressed areas (OR: 1.08 per 10 extra points over 100; 95%CI: 1.04-1.12), smokers (OR: 2.2; 95%CI: 1.9-2.6), and those with more children (OR: 1.2 for each sibling; 95%CI: 1.1-1.3), preterm birth (OR: 1.8; 95%CI: 1.4-2.3), multiple births (OR: 1.6; 95%CI: 1.2-2.1) and a higher risk pregnancy (OR: 1.3 per risk point; 95%CI: 1.2-1.4) showed a higher prevalence of IL. Compared to women born in Spain, IL was less likely in all other women with the exception of Chinese women (OR: 7.0; 95%CI: 5.7-8.6). These disparities remained during the study period. CONCLUSIONS: Factors related to lower socioeconomic status and poor health were more likely to be associated with IL. The overall use of cabergoline decreased during the study period while inequalities persisted. Taking these inequalities into account is the first step to addressing them.

Latency to delivery in physical examination-indicated cerclage in twins is similar to that in singleton pregnancies.

OBJECTIVE: To compare latency to delivery and perinatal outcomes between twin and singleton pregnancies undergoing physical examination-indicated cerclage. METHODS: Retrospective observational study (2007-2017) of women who underwent physical examination-indicated cerclage at the Hospital Clinic of Barcelona. Primary outcomes were latency from cerclage to delivery and gestational age at delivery. Secondary outcomes included: neonatal morbidity and mortality, preterm prelabor rupture of membranes, clinical chorioamnionitis and cerclage displacement. Wilcoxon-test and χ2 test were used to compare continuous and categorical variables. RESULTS: Sixty women were included (17 twins and 43 singletons). There were no differences in gestational age at cerclage or presence of bulging membranes between groups. Median (25th;75th percentile) gestational age at delivery was 27.1 (24.5;32.3) weeks in the twin group and 27.6 (25.3;35.3) weeks in the singleton group (P = 0.594). There were no statistically significant differences in latency from cervical cerclage to delivery between the two groups (43 days [21;64] vs. 29 days [16;76], respectively; P = 0.938). There were no differences in neonatal mortality (2/26 [7.7%] vs. 1/33 [3.1%]; P = 0.578) or in composite neonatal morbidity (14 [53.9%] vs. 14 [42.4%]; P = 0.283) between groups, respectively. CONCLUSION: These results suggest that physical examination-indicated cerclage placement in twins could prolong latency to delivery similarly to singleton pregnancies.

Retinal Protection from LED-Backlit Screen Lights by Short Wavelength Absorption Filters.

(1) Background: Ocular exposure to intense light or long-time exposure to low-intensity short-wavelength lights may cause eye injury. Excessive levels of blue light induce photochemical damage to the retinal pigment and degeneration of photoreceptors of the outer segments. Currently, people spend a lot of time watching LED screens that emit high proportions of blue light. This study aims to assess the effects of light emitted by LED tablet screens on pigmented rat retinas with and without optical filters. (2) Methods: Commercially available tablets were used for exposure experiments on three groups of rats. One was exposed to tablet screens, the other was exposed to the tablet screens with a selective filter and the other was a control group. Structure, gene expression (including life/death, extracellular matrix degradation, growth factors, and oxidative stress related genes), and immunohistochemistry in the retina were compared among groups. (3) Results: There was a reduction of the thickness of the external nuclear layer and changes in the genes involved in cell survival and death, extracellular matrix turnover, growth factors, inflammation, and oxidative stress, leading decrease in cell density and retinal damage in the first group. Modulation of gene changes was observed when the LED light of screens was modified with an optical filter. (4) Conclusions: The use of short-wavelength selective filters on the screens contribute to reduce LED light-induced damage in the rat retina.