Dysregulation of miRNA-mRNA expression in fetal growth restriction in a caloric restricted mouse model.

Fetal growth restriction (FGR) is associated with aberrant placentation and accounts for a significant proportion of perinatal deaths. microRNAs have been shown to be dysregulated in FGR. The purpose of this study was to determine microRNA-regulated molecular pathways altered using a caloric restricted mouse model of FGR. Pregnant mice were subjected to a 50% caloric restricted diet beginning at E9. At E18.5, RNA sequencing of placental tissue was performed to identify differences in gene expression between caloric restricted and control placentas. Significant differences in gene expression between caloric restricted and control placentas were observed in 228 of the 1546 (14.7%) microRNAs. Functional analysis of microRNA-mRNA interactions demonstrated enrichment of several biological pathways with oxidative stress, apoptosis, and autophagy pathways upregulated and angiogenesis and signal transduction pathways downregulated. Ingenuity pathway analysis also suggested that ID1 signaling, a pathway integral for trophoblast differentiation, is also dysregulated in caloric restricted placentas. Thus, a maternal caloric restriction mouse model of FGR results in aberrant microRNA-regulated molecular pathways associated with angiogenesis, oxidative stress, signal transduction, apoptosis, and cell differentiation. As several of these pathways are dysregulated in human FGR, our findings suggest that this model may provide an excellent means to study placental microRNA derangements seen in FGR.

Metabolic and fecal microbial changes in adult fetal growth restricted mice.

BACKGROUND: Fetal growth restriction (FGR) increases risk for development of obesity and type 2 diabetes. Using a mouse model of FGR, we tested whether metabolic outcomes were exacerbated by high-fat diet challenge or associated with fecal microbial taxa. METHODS: FGR was induced by maternal calorie restriction from gestation day 9 to 19. Control and FGR offspring were weaned to control (CON) or 45% fat diet (HFD). At age 16 weeks, offspring underwent intraperitoneal glucose tolerance testing, quantitative MRI body composition assessment, and energy balance studies. Total microbial DNA was used for amplification of the V4 variable region of the 16 S rRNA gene. Multivariable associations between groups and genera abundance were assessed using MaAsLin2. RESULTS: Adult male FGR mice fed HFD gained weight faster and had impaired glucose tolerance compared to control HFD males, without differences among females. Irrespective of weaning diet, adult FGR males had depletion of Akkermansia, a mucin-residing genus known to be associated with weight gain and glucose handling. FGR females had diminished Bifidobacterium. Metabolic changes in FGR offspring were associated with persistent gut microbial changes. CONCLUSION: FGR results in persistent gut microbial dysbiosis that may be a therapeutic target to improve metabolic outcomes. IMPACT: Fetal growth restriction increases risk for metabolic syndrome later in life, especially if followed by rapid postnatal weight gain. We report that a high fat diet impacts weight and glucose handling in a mouse model of fetal growth restriction in a sexually dimorphic manner. Adult growth-restricted offspring had persistent changes in fecal microbial taxa known to be associated with weight, glucose homeostasis, and bile acid metabolism, particularly Akkermansia, Bilophilia and Bifidobacteria. The gut microbiome may represent a therapeutic target to improve long-term metabolic outcomes related to fetal growth restriction.

Angiogenic and Inflammatory microRNA Regulation in a Mouse Model of Fetal Growth Restriction.

INTRODUCTION: Fetal growth restriction (FGR) is associated with impaired angiogenesis and chronic inflammation. MicroRNAs (miRs) are short noncoding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNA (mRNA) for degradation or by suppressing translation. We hypothesize that dysregulation of miR-15b, an antiangiogenic miR, and miR-146a, an anti-inflammatory miR, are associated with the FGR's pathogenesis. METHODS: Pregnant mice were provided ad libitum access to food between E1 and E8. From E9-E18, dams received either a 50% caloric restricted diet (FGR) or continued ad libitum access (controls). Placentas were harvested at E18.5 and total RNA was extracted. Gene expression levels of miRs and mRNAs were compared between FGR and control placentas. RESULTS: Placentas affected by FGR demonstrated increased expression of miR-15b. Vascular endothelial growth factor alpha, which is downregulated in response to increased levels of miR-15b, was suppressed. The anti-inflammatory miR, miR-146a, was downregulated, resulting in upregulation of proinflammatory (IL-6, IL-8, and NFkB1) and oxidative stress (HIF-1α, SOD2, and Nox2) mediators. CONCLUSIONS: Aberrant angiogenesis and chronic inflammation seen in FGR appear to be associated with dysregulated miR-15b and miR-146a gene expression, respectively. This observation suggests these miRs play a post-transcriptional regulatory role in FGR, providing an insight into possible therapeutic targets.

Changes in the community structure of stony corals in the southern Mexican Caribbean.

The Mexican Caribbean coral reef ecosystem has endured the effects of global and regional stressors and, recently, the massive arrivals of the free-living, floating brown algae Sargassum spp. This study aimed to evaluate spatiotemporal changes in the stony coral community structure in the southern Mexican Caribbean by a temporal comparison of live coral cover and colony density using a data set collected in 2008-2009 and a recent survey in 2021 within a Protected Natural Area. A multivariate analysis approach was used to reveal spatiotemporal changes in coral cover and colony densities. Coral cover ranged from 6.9 to 8.9% in 2008-2009 to 6.5% in 2021, the lowest values recorded for the area. Coral colony density ranged from 0.68 to 0.78 colonies m-1 in 2008-2009 to 0.68 colonies m-1 in 2021. The present results appear to represent subtle changes during the last decade.

Traumatic scalp arteriovenous fistula post capillary implantation successfully treated using PHIL embolic agent.

Background: A traumatic arteriovenous fistula of the scalp due to hair transplantation (AVFHT) is a rare fistulous communication between branches of the arteries and draining veins in the scalp's subcutaneous tissue. Its incidence is unknown and its clinical manifestations may range from a pulsatile mass to seldom epilepsy. Surgery and interventional approaches (percutaneous and endovascular embolization) using coils and embolic agents such as Onyx have been used as treatment options. The authors report a rare case of an AVFHT successfully treated through percutaneous and endovascular embolization using coils and precipitating hydrophobic injectable liquid (PHIL) embolic agent. This is possibly the first reported case using PHIL embolic agent to treat an AVFHT. Case Description: The patient presented with a painful and disabling scalp swelling in the right parieto-occipital region 2 years after a hair transplant in 2011. A computed tomography angiography showed an arteriovenous fistula between branches of the right superficial temporal artery and branches of the right occipital artery to the right superficial temporal vein that was successfully embolized using coils and PHIL. The patient was discharged after a smooth recovery and 1 month later remained healthy. Conclusion: Percutaneous and endovascular embolization using PHIL embolic agent can be an alternative treatment for AVFHT.

Stories told by corals, algae, and sea-urchins in a Mesoamerican coral reef: degradation trumps succession.

Understanding the mechanisms that allow the permanence of coral reefs and the constancy of their characteristics is necessary to alleviate the effects of chronic environmental changes. After a disturbance, healthy coral reefs display trajectories that allow regaining coral cover and the establishment of framework building corals. Through a comparative approach, in a patch reef partially affected by a ship grounding, we analyzed the successional trajectories in affected and unaffected sectors. Fleshy algae (which do not promote the recruitment of corals) dominated the reef surface irrespective of the impact of the ship grounding incident. Acropora species had near-zero contributions to community structure, whereas non-framework building corals like Porites sp. had a slightly higher recruitment. Cover of coral and calcareous crustose algae decreased over time, and neither the latter nor adult coral colonies had any effect on the occurrence probabilities of small corals. Sea urchin (Diadema antillarum) densities were generally low, and thus unlikely to contribute to reverting algal dominance. The successional trajectories of the community in the impacted and non-impacted sectors of the coral patch reef agree with the inhibition successional model, leading to the development of a degraded state dominated by fleshy algae. It is probable that the stability and resilience of this degraded state are high due to the ability of fleshy algae to monopolize space, along with low coral recovery potential.

Why honeybees are poor pollinators of a mass-flowering plant: Experimental support for the low pollen quality hypothesis.

PREMISE: Honeybees dominate the flower-visitor assemblages of many plant species, yet their efficiency in terms of the quality of pollen delivered to stigmas is largely unknown. We investigated why honeybees are poor pollinators of Aloe ferox, a self-incompatible succulent treelet with large numbers of flowers. Honeybees are very frequent visitors to flowers of this species, yet contribute very little to seed production. METHODS: We assessed pollen loads on honeybees, studied their visitation behavior, selectively excluded birds from plants to determine direct effects of bees on pollen deposition, seed set, and ovule abortion, and used a novel "split-pollinator" method to test whether honeybees deposit mainly low-quality self pollen. For the latter, we captured honeybees, and with their existing pollen loads, used them to either pollinate virgin flowers on the plant on which they were caught or to pollinate virgin flowers on different plants. RESULTS: Honeybees cumulatively deposit as much pollen on stigmas as do birds, but our experiments showed that the pollen deposited by honeybees is mostly low-quality self pollen that leads to substantial ovule discounting and depressed seed set. CONCLUSIONS: Lack of movement among A. ferox plants during individual honeybee foraging bouts is the most likely explanation for their deposition of low-quality self pollen on stigmas. The "split-pollinator" method is a simple and cost-effective technique to test the quality of pollination.

[Epidemiological characteristics of workers with COVID-19 from the Instituto Mexicano del Seguro Social]. / Características epidemiológicas de trabajadores con COVID-19 del Instituto Mexicano del Seguro Social.

Background: ¿In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of the respiratory disease called COVID-19, in Wuhan, China. At the end of February 2020, it was detected in Mexico the first case of COVID-19. With this disease, chronic degenerative diseases are decisive for comorbidity to continue increasing. Objective: To know the epidemiological characteristics and comorbidity in workers sick with COVID-19 from the Veracruz Norte Regional Deconcentrated Administrative Operation Body, from the Mexican Institute for Social Security (Instituto Mexicano del Seguro Social, IMSS). Material and methods: Descriptive, cross-sectional study, which included 228 COVID-19 patients, who were IMSS workers. Variables such as age, gender, as well as medical unit, contractual category, comorbidities, etc., were analyzed and were taken from April to June 2020 from the Online Notification System for Epidemiological Surveillance (SINOLAVE) database. It was used descriptive statistics, and Pearson's chi-squared, with a p < 0.05. Results: 228 patients were analyzed. The nursing staff was the one with the highest prevalence with 101 patients (44.3%). Comorbidities such as obesity in the foreground, with 27 patients (11.8%), and diabetes mellitus alone with 15 patients (6.6%), and as a group, along with arterial hypertension, obesity and being a chronic smoker in 22 patients (9.6%) were the most frequent. Conclusions: The nursing staff predominated; the prevalent comorbidities were obesity, diabetes mellitus and arterial hypertension.

Introducción: en diciembre de 2019, el coronavirus 2 causante del síndrome respiratorio agudo severo (SARS-CoV-2) provocó un brote en Wuhan, China, de la enfermedad respiratoria denominada COVID-19. A finales de febrero de 2020 se detectó en México el primer caso de COVID-19. Con esta enfermedad, las enfermedades crónicas degenerativas son determinantes para que la comorbilidad continúe en aumento. Objetivo: conocer las características epidemiológicas y la comorbilidad en trabajadores enfermos de COVID-19 del Órgano de Operación Administrativa Desconcentrada Estatal Veracruz Norte, del Instituto Mexicano del Seguro Social (IMSS). Material y métodos: estudio descriptivo y transversal que incluyó a 228 pacientes de COVID-19, trabajadores del IMSS. Se analizaron variables como edad, género, así como unidad médica, categoría contractual, comorbilidades, etcétera, las cuales se tomaron de abril a junio de 2020 de la base del Sistema de Notificación en Línea para la Vigilancia Epidemiológica (SINOLAVE). Se empleó estadística descriptiva y chi cuadrada de Pearson, con una p < 0.05. Resultados: se analizaron 228 pacientes. El personal de enfermería fue el de mayor prevalencia, con 101 pacientes (44.3%). Las comorbilidades más frecuentes fueron la obesidad en primer plano, con 27 pacientes (11.8%), y la diabetes mellitus por sí sola con 15 (6.6%), y en conjunto, con hipertensión arterial, obesidad y ser fumador crónico se presentaron en 22 pacientes (9.6 %). Conclusiones: predominó el personal de enfermería; las comorbilidades prevalentes fueron la obesidad, la diabetes mellitus y la hipertensión arterial.

APAP-Induced IκBß/NFκB Signaling Drives Hepatic Il6 Expression and Associated Sinusoidal Dilation.

Acetaminophen (APAP) overdose results in high morbidity and mortality, with limited treatment options. Increased understanding of the cellular signaling pathways activated in response to toxic APAP exposure is needed to provide insight into novel therapeutic strategies. Toxic APAP exposure induces hepatic nuclear factor kappa B (NFκB) activation. NFκB signaling has been identified to mediate the proinflammatory response but also induces a prosurvival and regenerative response. It is currently unknown whether potentiating NFkB activation would be injurious or advantageous after APAP overdose. The NFκB inhibitory protein beta (IκBß) dictates the duration and degree of the NFκB response following exposure to oxidative injuries. Thus, we sought to determine whether IκBß/NFκB signaling contributes to APAP-induced hepatic injury. At late time points (24 h) following toxic APAP exposures, mice expressing only IκBß knock-in mice (AKBI mice) exhibited increased serologic evidence of hepatic injury. This corresponded with increased histologic injury, specifically related to sinusoidal dilatation. When compared with wild type mice, AKBI mice demonstrated sustained hepatic nuclear translocation of the NFκB subunits p65 and p50, and enhanced NFκB target gene expression. This included increased expression of interleukin-6 (Il-6), a known contributor to hepatic sinusoidal dilation. This transcriptional response corresponded with increased plasma protein content of Il-6, as well as increased activation of signal transducer and activator of transcription 3.

Características epidemiológicas de trabajadores con COVID-19 del Instituto Mexicano del Seguro Social / Epidemiological characteristics of workers with COVID-19 from the Instituto Mexicano del Seguro Social

Introducción: en diciembre de 2019, el coronavirus 2 causante del síndrome respiratorio agudo severo (SARS-CoV-2) provocó un brote en Wuhan, China, de la enfermedad respiratoria denominada COVID-19. A finales de febrero de 2020 se detectó en México el primer caso de COVID-19. Con esta enfermedad, las enfermedades crónicas degenerativas son determinantes para que la comorbilidad continúe en aumento. Objetivo: conocer las características epidemiológicas y la comorbilidad en trabajadores enfermos de COVID-19 del Órgano de Operación Administrativa Desconcentrada Estatal Veracruz Norte, del Instituto Mexicano del Seguro Social (IMSS). Material y métodos: estudio descriptivo y transversal que incluyó a 228 pacientes de COVID-19, trabajadores del IMSS. Se analizaron variables como edad, género, así como unidad médica, categoría contractual, comorbilidades, etcétera, las cuales se tomaron de abril a junio de 2020 de la base del Sistema de Notificación en Línea para la Vigilancia Epidemiológica (SINOLAVE). Se empleó estadística descriptiva y chi cuadrada de Pearson, con una p < 0.05. Resultados: se analizaron 228 pacientes. El personal de enfermería fue el de mayor prevalencia, con 101 pacientes (44.3%). Las comorbilidades más frecuentes fueron la obesidad en primer plano, con 27 pacientes (11.8%), y la diabetes mellitus por sí sola con 15 (6.6%), y en conjunto, con hipertensión arterial, obesidad y ser fumador crónico se presentaron en 22 pacientes (9.6 %). Conclusiones: predominó el personal de enfermería; las comorbilidades prevalentes fueron la obesidad, la diabetes mellitus y la hipertensión arterial

Background: In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of the respiratory disease called COVID-19, in Wuhan, China. At the end of February 2020, it was detected in Mexico the first case of COVID-19. With this disease, chronic degenerative diseases are decisive for comorbidity to continue increasing. Objective: To know the epidemiological characteristics and comorbidity in workers sick with COVID-19 from the Veracruz Norte Regional Deconcentrated Administrative Operation Body, from the Mexican Institute for Social Security (Instituto Mexicano del Seguro Social, IMSS). Material and methods: Descriptive, cross-sectional study, which included 228 COVID-19 patients, who were IMSS workers. Variables such as age, gender, as well as medical unit, contractual category, comorbidities, etc., were analyzed and were taken from April to June 2020 from the Online Notification System for Epidemiological Surveillance (SINOLAVE) database. It was used descriptive statistics, and Pearson's chi-squared, with a p < 0.05. Results: 228 patients were analyzed. The nursing staff was the one with the highest prevalence with 101 patients (44.3%). Comorbidities such as obesity in the foreground, with 27 patients (11.8%), and diabetes mellitus alone with 15 patients (6.6%), and as a group, along with arterial hypertension, obesity and being a chronic smoker in 22 patients (9.6%) were the most frequent. Conclusions: The nursing staff predominated; the prevalent comorbidities were obesity, diabetes mellitus and arterial hypertension

The Acute Hepatic NF-κB-Mediated Proinflammatory Response to Endotoxemia Is Attenuated in Intrauterine Growth-Restricted Newborn Mice.

Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors.

Pulmonary implications of acetaminophen exposures independent of hepatic toxicity.

Both preclinical and clinical studies have demonstrated that exposures to acetaminophen (APAP) at levels that cause hepatic injury cause pulmonary injury as well. However, whether exposures that do not result in hepatic injury have acute pulmonary implications is unknown. Thus, we sought to determine how APAP exposures at levels that do not result in significant hepatic injury impact the mature lung. Adult male ICR mice (8-12 wk) were exposed to a dose of APAP known to cause hepatotoxicity in adult mice [280 mg/kg, intraperitoneal (ip)], as well as a lower dose previously reported to not cause hepatic injury (140 mg/kg, ip). We confirm that the lower dose exposures did not result in significant hepatic injury. However, like high dose, lower exposure resulted in increased cellular content of the bronchoalveolar lavage fluid and induced a proinflammatory pulmonary transcriptome. Both the lower and higher dose exposures resulted in measurable changes in lung morphometrics, with the lower dose exposure causing alveolar wall thinning. Using RNAScope, we were able to detect dose-dependent, APAP-induced pulmonary Cyp2e1 expression. Finally, using FLIM we determined that both APAP exposures resulted in acute pulmonary metabolic changes consistent with mitochondrial overload in lower doses and a shift to glycolysis at a high dose. Our findings demonstrate that APAP exposures that do not cause significant hepatic injury result in acute inflammatory, morphometric, and metabolic changes in the mature lung. These previously unreported findings may help explain the potential relationship between APAP exposures and pulmonary-related morbidity.

Neonatal Selenoenzyme Expression Is Variably Susceptible to Duration of Maternal Selenium Deficiency.

Maternal selenium (Se) deficiency is associated with decreased neonatal Se levels, which increases the risk for neonatal morbidities. There is a hierarchy to selenoprotein expression after Se deficiency in adult rodents, depending on the particular protein and organ evaluated. However, it is unknown how limited Se supply during pregnancy impacts neonatal selenoprotein expression. We used an Se-deficient diet to induce perinatal Se deficiency (SeD), initiated 2-4 weeks before onset of breeding and continuing through gestation. Neonatal plasma, liver, heart, kidney, and lung were collected on the day of birth and assessed for selenoproteins, factors required for Se processing, and non-Se containing antioxidant enzymes (AOE). Maternal SeD reduced neonatal circulating and hepatic glutathione peroxidase (GPx) activity, as well as hepatic expression of Gpx1 and selenophosphate synthetase 2 (Sps2). In contrast, the impact of maternal SeD on hepatic thioredoxin reductase 1, hepatic non-Se containing AOEs, as well as cardiac, renal, and pulmonary GPx activity, varied based on duration of maternal exposure to SeD diet. We conclude that the neonatal liver and circulation demonstrate earlier depletion in selenoenzyme activity after maternal SeD. Our data indicate that prolonged maternal SeD may escalate risk to the neonate by progressively diminishing Se-containing AOE across multiple organs.

Food Reward Chemistry Explains a Novel Pollinator Shift and Vestigialization of Long Floral Spurs in an Orchid.

During the evolutionary history of flowering plants, transitions between pollinator groups (pollinator shifts) have been frequent,1 and contributed to the spectacular radiation of angiosperms.2 Although the evolution of floral traits during pollinator shifts has been studied in real time under controlled laboratory conditions,3 it is challenging to study in nature and therefore poorly understood.4-7 Using a comparative, multidisciplinary approach, we dissect the evolution of floral traits during a pollinator shift in the long-spurred African orchid Satyrium longicauda. Phylogenetic analysis and ecological experiments revealed a shift from moth- to oil-collecting bee pollination. Remarkably, flowers of the bee-pollinated form are similar in morphology, color, and overall volatile chemistry to those of moth-pollinated forms, but differ in having spurs that are mostly devoid of nectar, and have an elevated presence of the oil-derived compound diacetin, which oil-collecting bees use as a cue for oil presence.8 Experiments demonstrated that long spurs are critical for pollination of a moth-pollinated form, but are not needed for pollination of the bee-pollinated form. We conclude that the pollinator shift in Satyrium was mediated by a switch in chemistry of the pollinator reward. The ancestral presence of diacetin might have served as a pre-adaptation for bee pollination, whereas the current mismatch between flower morphology and bees is due to the retention of vestigial floral spurs. These results elucidate the sequence of floral evolution in the early stages of pollinator shifts and help to explain the assembly of suites of co-varying traits through pre-adaptation and vestigialization.9-12.

Maturation of the Acute Hepatic TLR4/NF-κB Mediated Innate Immune Response Is p65 Dependent in Mice.

Compared to adults, neonates are at increased risk of infection. There is a growing recognition that dynamic qualitative and quantitative differences in immunity over development contribute to these observations. The liver plays a key role as an immunologic organ, but whether its contribution to the acute innate immune response changes over lifetime is unknown. We hypothesized that the liver would activate a developmentally-regulated acute innate immune response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic expression and activity of the NF-κB, a key regulator of the innate immune response, at different developmental ages (p0, p3, p7, p35, and adult). Ontogeny of the NF-κB subunits (p65/p50) revealed a reduction in Rela (p65) and Nfkb1 (p105, precursor to p50) gene expression (p0) and p65 subunit protein levels (p0 and p3) vs. older ages. The acute hepatic innate immune response to LPS was associated by the degradation of the NF-κB inhibitory proteins (IκBα and IκBß), and nuclear translocation of the NF-κB subunit p50 in all ages, whereas nuclear translocation of the NF-κB subunit p65 was only observed in the p35 and adult mouse. Consistent with these findings, we detected NF-κB subunit p65 nuclear staining exclusively in the LPS-exposed adult liver compared with p7 mouse. We next interrogated the LPS-induced hepatic expression of pro-inflammatory genes (Tnf, Icam1, Ccl3, and Traf1), and observed a gradually increase in gene expression starting from p0. Confirming our results, hepatic NF-κB subunit p65 nuclear translocation was associated with up-regulation of the Icam1 gene in the adult, and was not detected in the p7 mouse. Thus, an inflammatory challenge induces an NF-κB-mediated hepatic innate immune response activation across all developmental ages, but nuclear translocation of the NF-κB subunit p65 and associated induction of pro-inflammatory genes occurred only after the first month of life. Our results demonstrate that the LPS-induced hepatic innate immune response is developmentally regulated by the NF-κB subunit p65 in the mouse.

Dextrose Prolotherapy Versus Lidocaine Injection for Temporomandibular Dysfunction: A Pragmatic Randomized Controlled Trial.

Objective: Several intraarticular injections, including dextrose and lidocaine, are reported to reduce pain and dysfunction in temporomandibular dysfunction (TMD) and increase maximal jaw opening; our goal was to determine whether dextrose/lidocaine outperforms sterile water/lidocaine for TMD. Design: Pragmatic randomized controlled trial. Setting: Outpatient clinic. Subjects: Chronic (≥3 months) of moderate-to-severe (≥6/10) jaw or facial pain meeting research-specific TMD criteria. Intervention: Blinded intraarticular dextrose prolotherapy (DPT) (20% dextrose/0.2% lidocaine) versus intraarticular lidocaine (0.2% lidocaine in sterile water) at 0, 1, and 2 months. Participants were then unblinded and offered DPT by request for 9 additional months. Main outcome measures: Primary: Numerical Rating Scale (0-10 points) score for facial pain and jaw dysfunction; percentage achieving ≥50% improvement in pain and dysfunction (0, 3, and 12 months). Secondary: Maximal interincisal opening (MIO; 0 and 3 months). Intention-to-treat analysis was by joint using mixed-model regression. Results: Randomization of 29 participants (25 female, 47 ± 17 years, 43 joints) produced similar groups. Three-month pain and dysfunction improvements were similar, but more DPT-treated joints improved by ≥50% in pain (17/22 vs. 6/21; p = 0.028). The MIO improved in both groups (5.6 ± 5.8 mm vs. 5.1 ± 7.0 mm; p = 0.70). From 3 to 12 months, minimal DPT was received by original DPT and lidocaine recipients, 0.5 ± 0.9 and 0.6 ± 1.5 injections, respectively, with only 2 out of 21 joints in the original lidocaine group receiving more than 1 dextrose injection after 3 months. Twelve-month analysis revealed that joints in the original DPT group improved more in jaw pain (4.8 ± 2.4 points vs. 2.6 ± 2.9 points; p = 0.026) and jaw dysfunction (5.3 ± 2.6 points vs. 2.7 ± 2.3 points; p = 0.013). More DPT than lidocaine-treated joints improved by ≥50% in both pain (19/22 vs. 5/21; p = 0.003) and dysfunction (17/22 vs. 7/21; p = 0.040). There were no adverse events; satisfaction was high. Conclusions: Intraarticular DPT resulted in clinically important and statistically significant improvement in pain and dysfunction at 12 months compared to lidocaine injection (ClinicalTrials.gov identifier NCT01617356).

In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep.

Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.

Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling.

The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBß, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBß. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.

La proloterapia mostró buenos resultados para aliviar el dolor de pacientes con síndrome de disfunción músculo tendinosa del trocánter mayor: cohorte prospectiva / Prolotherapy showed good results to relieve pain of patients with tendon-muscle dysfunction syndrome of the greater trochanter: prospective case series

OBJETIVOS: Describir la evolución de una cohorte de pacientes con sindrome de disfunción dolorosa del trocánter mayor tratados con proloterapia. MÉTODOS: 30 pacientes con dolor crónico recibieron una mediana de 3,5 inyecciones de dextrosa al 12,5% y lidocaina al 0,5% en la entesis de los músculos que se insertan en el trocanter mayor. Fueron evaluados sus cambios en el dolor mediante una escala analógica visual (EAV) y en la calidad de vida, a través del puntaje Euro Quol 5D. RESULTADOS: A los seis meses de la primera inyección se constató una reducción media del dolor de 5,45 (IC 95% 4,55 a 6,34) puntos de la EAV, desde una media basal de 8,01 (5 a 10) a una media a los seis meses de 2,56 (1 a 7); y una mejoría de la calidad de vida desde 0,401 a 0,891 puntos en la escala Euro Quol 5D. No se observaron efectos adversos. CONCLUSIÓN: Los pacientes con sindrome de disfunción dolorosa del trocánter mayor tratados con proloterapia evolucionaron con una reducción en su nivel de dolor y una mejoría en su calidad (AU)

OBJECTIVES: To describe the evolution of a cohort of patients with a major trochanter dysfunction pain syndrome treated with prolotherapy. METHODS: 30 patients with chronic pain received a median of 3.5 injections of 12.5% dextrose and 0.5% lidocaine in the entesis of the muscles that are inserted into the greater trocanter. Their changes in pain were assessed using a visual analogue scale (VAS) and quality of life, through the Euro Quol 5D score. RESULTS: Six months after the first injection, a mean pain reduction of 5.45 (95% CI 4.55 to 6.34) VAS points was observed, from a baseline average of 8.01 (5 to 10 ) to an average of 2.56 (1 to 7) at six-month; and an improvement in the quality of life from 0.401 to 0.891 points on the Euro Quol 5D scale. No adverse effects were observed. CONCLUSION: Patients with major trochanter dysfunction pain syndrome treated with prolotherapy evolved with a reduction in their level of pain and an improvement in their quality of life (AU)