Systematic review and meta-analysis of birth weight and perfluorohexane sulfonate exposures: examination of sample timing and study confidence.

We examined the association between mean birth weight (BW) differences and perfluorohexane sulfonate (PFHxS) exposure biomarkers.We fit a random effects model to estimate the overall pooled effect and for different strata based on biomarker sample timing and overall study confidence. We also conducted an analysis to examine the impact of a continuous measure of gestational age sample timing on the overall pooled effect.We detected a -7.9 g (95% CI -15.0 to -0.7; pQ=0.85; I2=0%) BW decrease per ln ng/mL PFHxS increase based on 27 studies. The 11 medium confidence studies (ß=-10.0 g; 95% CI -21.1 to 1.1) showed larger deficits than 12 high (ß=-6.8 g; 95% CI -16.3 to 2.8) and 4 low confidence studies (ß=-1.5 g; 95% CI -51.6 to 48.7). 10 studies with mid-pregnancy to late-pregnancy sampling periods showed smaller deficits (ß=-3.9 g; 95% CI -17.7 to 9.9) than 5 post-partum studies (ß=-28.3 g; 95% CI -69.3 to 12.7) and 12 early sampling studies (ß=-7.6 g; 95% CI -16.2 to 1.1). 6 of 12 studies with the earliest sampling timing showed results closer to the null.Overall, we detected a small but statistically significant BW deficit across 27 studies. We saw comparable BW deficit magnitudes in both the medium and high confidence studies as well as the early pregnancy group. Despite no definitive pattern by sample timing, larger deficits were seen in postpartum studies. We also saw results closer to the null for a subset of studies restricted to the earliest biomarker collection times. Serial pregnancy sampling, improved precision in gestational age estimates and more standardised reporting of sample variation and exposure units in future epidemiologic research may offer a greater understanding of the relationship between PFHxS on BW and any potential impact of pregnancy haemodynamics.

Chronic sucralose consumption inhibits farnesoid X receptor signaling and perturbs lipid and cholesterol homeostasis in the mouse livers, potentially by altering gut microbiota functions.

Sucralose has raised concerns regarding its safety and recent studies have demonstrated that sucralose consumption can disrupt the normal gut microbiome and alter metabolic profiles in mice. However, the extent to which this perturbation affects the functional interaction between the microbiota and the host, as well as its potential impact on host health, remains largely unexplored. Here, we aimed to investigate whether chronic sucralose consumption, at levels within the Acceptable Daily Intake (ADI), could disturb key gut microbial functions and lead to adverse health effects in mice. Following six-month sucralose consumption, several bacterial genera associated with bile acid metabolism were decreased, including Lactobacillus and Ruminococcus. Consequently, the richness of secondary bile acid biosynthetic pathway and bacterial bile salt hydrolase gene were decreased in the sucralose-treated gut microbiome. Compared to controls, sucralose-consuming mice exhibited significantly lower ratios of free bile acids and taurine-conjugated bile acids in their livers. Additionally, several farnesoid X receptor (FXR) agonists were decreased in sucralose-treated mice. This reduction in hepatic FXR activation was associated with altered expression of down-stream genes, in the liver. Moreover, the expression of key lipogenic genes was up-regulated in the livers of sucralose-treated mice. Changes in hepatic lipid profiles were also observed, characterized by lower ceramide levels, a decreased PC/PE ratio, and a mildly increase in lipid accumulation. Additionally, sucralose-consumed mice exhibited higher hepatic cholesterol level compared to control mice, with up-regulation of cholesterol efflux genes and down-regulation of genes associated with reverse cholesterol transport. In conclusion, chronic sucralose consumption disrupts FXR signaling activation and perturbs hepatic lipid and cholesterol homeostasis, potentially by diminishing the bile acid metabolic capacity of the gut microbiome. These findings shed light on the complex interplay between sucralose, the gut microbiota, and host metabolism, raising important questions about the safety of its long-term consumption.

A Black Raspberry-Rich Diet Protects From Dextran Sulfate Sodium-Induced Intestinal Inflammation and Host Metabolic Perturbation in Association With Increased Aryl Hydrocarbon Receptor Ligands in the Gut Microbiota of Mice.

Dietary modulation of the gut microbiota recently received considerable attention, and ligand activation of aryl hydrocarbon receptor (AHR) plays a pivotal role in intestinal immunity. Importantly, black raspberry (BRB, Rubus occidentalis) is associated with a variety of beneficial health effects. We aim to investigate effects of a BRB-rich diet on dextran sulfate sodium (DSS)-induced intestinal inflammation and to determine whether its consequent anti-inflammatory effects are relevant to modulation of the gut microbiota, especially its production of AHR ligands. A mouse model of DSS-induced intestinal inflammation was used in the present study. C57BL/6J mice were fed either AIN-76A or BRB diet. Composition and functions of the gut microbiota were assessed by 16S rRNA sequencing and comparative metagenome analysis. Metabolic profiles of host and the gut microbiome were assessed by serum and fecal metabolomic profiling and identification. BRB diet was found to ameliorate DSS-induced intestinal inflammation and host metabolic perturbation. BRB diet also protected from DSS-induced perturbation in diversity and composition in the gut microbiota. BRB diet promoted AHR ligand production by the gut microbiota, as revealed by increased levels of fecal AHR activity in addition to increased levels of two known AHR ligands, hemin and biliverdin. Accordingly, enrichment of bacterial genes and pathways responsible for production of hemin and biliverdin were found, specific gut bacteria that are highly correlated with abundances of hemin and biliverdin were also identified. BRB dietary intervention ameliorated intestinal inflammation in mice in association with promotion of AHR ligand production by the gut microbiota.

Psychiatric Outcomes, Functioning, and Participation in Extremely Low Gestational Age Newborns at Age 15 Years.

OBJECTIVE: To evaluate the prevalence, co-occurrence, sex differences, and functional correlates of DSM-5 psychiatric disorders in 15-year-old adolescents born extremely preterm. METHOD: The Extremely Low Gestational Age Newborns (ELGAN) Study is a longitudinal study of children born <28 weeks gestation. At age 15, 670 adolescents completed the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), the Youth Self-Report, a disability scale of participation in social roles, and cognitive testing. Parents completed a family psychiatric history questionnaire. RESULTS: The most prevalent psychiatric disorders were anxiety, attention-deficit/hyperactivity disorder, and major depression. More girls met criteria for anxiety than boys. Though 66% of participants did not meet criteria for a psychiatric disorder, 15% met criteria for 1, 9% for 2, and 8% for ≥3 psychiatric disorders. Participants with ≥2 psychiatric disorders were more likely to have repeated a grade, to have an individualized educational program, and to have a lower nonverbal IQ than those with no psychiatric disorders. Participants with any psychiatric disorder were more likely to use psychotropic medications; to have greater cognitive and functional impairment; and to have mothers who were single, were on public health insurance, and had less than a high school education. Finally, a positive family psychiatric history was identified more frequently among adolescents with ≥3 psychiatric disorders. CONCLUSION: Among adolescents born extremely preterm, anxiety, major depression, and attention-deficit/hyperactivity disorder were the most prevalent psychiatric disorders at age 15. Adolescents with >1 psychiatric disorder were at increased risk for multiple functional and participatory challenges.

High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice.

The mammalian gut harbors a complex and dynamic microbial ecosystem: the microbiota. While emerging studies support that microbiota regulates brain function with a few molecular cues suggested, the overall biochemical landscape of the "microbiota-gut-brain axis" remains largely unclear. Here we use high-coverage metabolomics to comparatively profile feces, blood sera, and cerebral cortical brain tissues of germ-free C57BL/6 mice and their age-matched conventionally raised counterparts. Results revealed for all three matrices metabolomic signatures owing to microbiota, yielding hundreds of identified metabolites including 533 altered for feces, 231 for sera, and 58 for brain with numerous significantly enriched pathways involving aromatic amino acids and neurotransmitters. Multicompartmental comparative analyses single out microbiota-derived metabolites potentially implicated in interorgan transport and the gut-brain axis, as exemplified by indoxyl sulfate and trimethylamine-N-oxide. Gender-specific characteristics of these landscapes are discussed. Our findings may be valuable for future research probing microbial influences on host metabolism and gut-brain communication.

Studies of xenobiotic-induced gut microbiota dysbiosis: from correlation to mechanisms.

Environmental chemicals can alter gut microbial community composition, known as dysbiosis. However, the gut microbiota is a highly dynamic system and its functions are still largely underexplored. Likewise, it is unclear whether xenobiotic exposure affects host health through impairing host-microbiota interactions. Answers to this question not only can lead to a more precise understanding of the toxic effects of xenobiotics but also can provide new targets for the development of new therapeutic strategies. Here, we aim to identify the major challenges in the field of microbiota-exposure research and highlight the need to exam the health effects of xenobiotic-induced gut microbiota dysbiosis in host bodies. Although the changes of gut microbiota frequently co-occur with the xenobiotic exposure, the causal relationship of xenobiotic-induced microbiota dysbiosis and diseases is rarely established. The high dynamics of the gut microbiota and the complex interactions among exposure, microbiota, and host, are the major challenges to decipher the specific health effects of microbiota dysbiosis. The next stage of study needs to combine various technologies to precisely assess the xenobiotic-induced gut microbiota perturbation and the subsequent health effects in host bodies. The exposure, gut microbiota dysbiosis, and disease outcomes have to be causally linked. Many microbiota-host interactions are established by previous studies, including signaling metabolites and response pathways in the host, which may use as start points for future research to examine the mechanistic interactions of exposure, gut microbiota, and host health. In conclusion, to precisely understand the toxicity of xenobiotics and develop microbiota-based therapies, the causal and mechanistic links of exposure and microbiota dysbiosis have to be established in the next stage study.

Neonatal Cranial Ultrasound Findings among Infants Born Extremely Preterm: Associations with Neurodevelopmental Outcomes at 10 Years of Age.

OBJECTIVE: To examine the association between neonatal cranial ultrasound (CUS) abnormalities among infants born extremely preterm and neurodevelopmental outcomes at 10 years of age. STUDY DESIGN: In a multicenter birth cohort of infants born at <28 weeks of gestation, 889 of 1198 survivors were evaluated for neurologic, cognitive, and behavioral outcomes at 10 years of age. Sonographic markers of white matter damage (WMD) included echolucencies in the brain parenchyma and moderate to severe ventricular enlargement. Neonatal CUS findings were classified as intraventricular hemorrhage (IVH) without WMD, IVH with WMD, WMD without IVH, and neither IVH nor WMD. RESULTS: WMD without IVH was associated with an increased risk of cognitive impairment (OR 3.5, 95% CI 1.7, 7.4), cerebral palsy (OR 14.3, 95% CI 6.5, 31.5), and epilepsy (OR 6.9; 95% CI 2.9, 16.8). Similar associations were found for WMD accompanied by IVH. Isolated IVH was not significantly associated these outcomes. CONCLUSIONS: Among children born extremely preterm, CUS abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Detection of gut microbiota and pathogen produced N-acyl homoserine in host circulation and tissues.

Recent studies suggest that quorum-sensing molecules may play a role in gut microbiota-host crosstalk. However, whether microbiota produces quorum-sensing molecules and whether those molecules can trans-kingdom transport to the host are still unknown. Here, we develop a UPLC-MS/MS-based assay to screen the 27 N-acyl homoserine lactones (AHLs) in the gut microbiota and host. Various AHL molecules are exclusively detected in the cecal contents, sera and livers from conventionally-raised mice but cannot be detected in germ-free mice. Pathogen-produced C4-HSL is detected in the cecal contents and sera of Citrobacter rodentium (C. rodentium)-infected mice, but not found in uninfected controls. Moreover, C. rodentium infection significantly increases the level of multiple AHL molecules in sera. Our findings demonstrate that both commensal and pathogenic bacteria, can produce AHLs that can be detected in host bodies, suggesting that quorum-sensing molecules could be a group of signaling molecules in trans-kingdom microbiota-host crosstalk.

Metabolites from midtrimester plasma of pregnant patients at high risk for preterm birth.

BACKGROUND: There is an increased awareness regarding the association between exposure to environmental contaminants and adverse pregnancy outcomes including preterm birth. Whether an individual's metabolic profile can be utilized during pregnancy to differentiate the subset of patients who are ultimately destined to delivered preterm remains uncertain but could have MEANINGFUL clinical implications. OBJECTIVE: We sought to objectively quantify metabolomic profiles of patients at high risk of preterm birth by evaluating midtrimester maternal plasma and to measure whether endogenous metabolites and exogenous environmental substances differ among those who ultimately deliver preterm compared with those who deliver at term. STUDY DESIGN: This was a case-control analysis from a prospective cohort of patients carrying a singleton, nonanomalous gestation who were at high risk of spontaneous preterm birth. Subjects with a plasma blood sample drawn at <28 weeks' gestation and no evidence of preterm labor at the time of enrollment were included. Metabolites were extracted from frozen samples, and metabolomic analysis was performed using liquid chromatography/mass spectrometry. The primary outcome was preterm birth at 16.0 to 36.9 weeks' gestation. RESULTS: A total of 42 patients met the inclusion criteria. Of these, 25 (59.5%) delivered preterm at <37 weeks' gestation, at a median of 30.14 weeks' gestation (interquartile range, 28.14-34.14). A total of 812 molecular features differed between preterm birth cases and term controls with a minimum fold change of 1.2 and P<.05. Of these, 570 of 812 (70.1%) were found in higher abundances in preterm birth cases; the other 242 of 812 (29.9%) were in higher abundance in term birth controls. The identity of the small molecule/compound represented by the molecular features differing statistically between preterm birth cases and term controls was identified as ranging from those involved with endogenous metabolic pathways (including lipid catabolism, steroids, and steroid-related molecules) to exogenous exposures (including avocadyne, diosgenin, polycyclic aromatic hydrocarbons, acetaminophen metabolites, aspartame, and caffeine). Random forest analyses evaluating the relative contribution of each of the top 30 compounds in differentiating preterm birth and term controls accurately classified 21 of 25 preterm birth cases (84%). CONCLUSION: Both endogenous metabolites and exogenous exposures differ in maternal plasma in the midtrimester among patients who ultimately delivered preterm compared with those who deliver at term.

High-Resolution Metabolomics of 50 Neurotransmitters and Tryptophan Metabolites in Feces, Serum, and Brain Tissues Using UHPLC-ESI-Q Exactive Mass Spectrometry.

Recent evidence indicates that tryptophan metabolites and neurotransmitters are potential mediators of the microbiome-gut-brain interaction. Here, a high-resolution ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) assay was developed and validated for quantifying 50 neurotransmitters, tryptophan metabolites, and bacterial indole derivatives in mouse serum, feces, and brain. The lower limit of quantitation for the 50 compounds ranged from 0.5 to 100 nmol/L, and sample preparation procedures were adapted for individual compounds to allow quantitation within linearity of the assay with a correlation coefficient >0.99. Reproducibility was tested by intra- and interday precision and accuracy of analysis: intra- and interday precision at the lower limit of quantitation was less than 20% for all compounds, with over two-thirds of the compounds achieving an interday precision below 10%, while the interday accuracy at the lower limit of quantitation ranged from 82.3 to 128.0% for all compounds. The analyte recovery was assessed based on sample-spiked stable-isotope-labeling standards, illustrating a need to consider matrix-specific recovery discrepancies when performing interorgan comparison. Carryover was evaluated by intermittent solvent blank injection. The assay was successfully applied to determining the concentration profiles of neurotransmitter and tryptophan metabolites in serum, feces, and brain of conventionally raised specific pathogen-free (SPF) C57BL/6 mice. Our method may serve as a useful analytical resource for investigating the roles of tryptophan metabolism and neurotransmitter signaling in host-microbiota interaction.

The gut microbiome and arsenic-induced disease-iAs metabolism in mice.

PURPOSE OF REVIEW: This review summarizes inorganic arsenic (iAs) metabolism and toxicity in mice and the gut microbiome and how iAs and the gut microbiome interact to induce diseases. RECENT FINDINGS: Recently, a variety of studies have started to reveal the interactions between iAs and the gut microbiome. Evidence shows that gut bacteria can influence iAs biotransformation and disease risks. The gut microbiome can directly metabolize iAs, and it can also indirectly be involved in iAs metabolism through the host, such as altering iAs absorption, cofactors, and genes related to iAs metabolism. Many factors, such as iAs metabolism influenced by the gut microbiome, and microbiome metabolites perturbed by iAs can lead to different disease risks. iAs is a widespread toxic metalloid in environment, and iAs toxicity has become a global health issue. iAs is subject to metabolic reactions after entering the host body, including methylation, demethylation, oxidation, reduction, and thiolation. Different arsenic species, including trivalent and pentavalent forms and inorganic and organic forms, determine their toxicity. iAs poisoning is predominately caused by contaminated drinking water and food, and chronic arsenic toxicity can cause various diseases. Therefore, studies of iAs metabolism are important for understanding iAs associated disease risks.

Association between anesthesia duration and outcome in dogs with surgically treated acute severe spinal cord injury caused by thoracolumbar intervertebral disk herniation.

BACKGROUND: Retrospective research recently identified a possible relationship between duration of surgery and outcome in severely affected dogs treated surgically for acute thoracolumbar intervertebral disk herniation (TL-IVDH). HYPOTHESIS: That increased duration of surgery is associated with poorer outcome in dogs with absent pain perception treated surgically for TL-IVDH. ANIMALS: Two hundred ninety-seven paraplegic dogs with absent pain perception surgically treated for acute TL-IVDH. METHODS: Retrospective cohort study. Medical records of 5 institutions were reviewed. Inclusion criteria were paraplegia with absence of pain perception, surgical treatment of TL-IVDH, and 1-year postoperative outcome (ambulatory: yes or no). Canine data, outcome, and surgery and total anesthesia duration were retrieved. RESULTS: In this study, 183/297 (61.6%) dogs were ambulatory within 1 year, 114 (38.4%) dogs failed to recover, including 74 dogs (24.9%) euthanized because of progressive myelomalacia. Median anesthesia duration in dogs that regained ambulation within 1 year of surgery (4.0 hours, interquartile range [IQR] 3.2-5.1) was significantly shorter than those that did not (4.5 hours, IQR 3.7-5.6, P = .01). Multivariable logistic regression demonstrated a significant negative association between both duration of surgery and total anesthesia time and ambulation at 1 year when controlling for body weight and number of disk spaces operated on. CONCLUSIONS AND CLINICAL IMPORTANCE: Findings support a negative association between increased duration of anesthesia and outcome in this group of dogs. However, the retrospective nature of the data does not imply a causal relationship.

Metabolite Profiling of the Gut Microbiome in Mice with Dietary Administration of Black Raspberries.

Mounting evidence has linked gut microbiome to health benefits of various functional foods. We previously reported that administration of a diet rich in black raspberry (BRB) changed the composition and diverse functional pathways in the mouse gut microbiome. To further characterize the functional profile in the gut microbiome of mice on BRB diet, in this follow-up study, we examined the metabolome differences in the gut microbiome driven by BRB consumption via targeted and untargeted metabolomic approaches. A distinct metabolite profile was observed in the gut microbiome of the mice on BRB diet, likely resulting from a combination of microbiome functional changes and unique precursors in BRBs. A number of functional metabolites, such as tetrahydrobiopterin and butyrate that were significantly increased in the gut microbiome may be linked to the beneficial health effects of BRB consumption. These findings suggest the important role of the gut microbiome in the health effects of BRBs and provide a connection among the health benefits of functional foods and the gut microbiome.

International lineages of Salmonella enterica serovars isolated from chicken farms, Wakiso District, Uganda.

The growing occurrence of multidrug-resistant (MDR) Salmonella enterica in poultry has been reported with public health concern worldwide. We reported, recently, the occurrence of Escherichia coli and Salmonella enterica serovars carrying clinically relevant resistance genes in dairy cattle farms in the Wakiso District, Uganda, highlighting an urgent need to monitor food-producing animal environments. Here, we present the prevalence, antimicrobial resistance, and sequence type of 51 Salmonella isolates recovered from 379 environmental samples from chicken farms in Uganda. Among the Salmonella isolates, 32/51 (62.7%) were resistant to at least one antimicrobial, and 10/51 (19.6%) displayed multiple drug resistance. Through PCR, five replicon plasmids were identified among chicken Salmonella isolates including IncFIIS 17/51 (33.3%), IncI1α 12/51 (23.5%), IncP 8/51 (15.7%), IncX1 8/51 (15.7%), and IncX2 1/51 (2.0%). In addition, we identified two additional replicons through WGS (Whole Genome Sequencing; ColpVC and IncFIB). A significant seasonal difference between chicken sampling periods was observed (p = 0.0017). We conclude that MDR Salmonella highlights the risks posed to animals and humans. Implementing a robust, integrated surveillance system will aid in monitoring MDR zoonotic threats.

A preoperative bupivacaine retrobulbar block offers superior antinociception compared with an intraoperative splash block in dogs undergoing enucleation.

PURPOSE: Investigate nociception differences in dogs undergoing enucleation administered bupivacaine either via preoperative retrobulbar block (pRB) or intraoperative splash block (iSB). METHODS: Prospective, randomized, double-masked, clinical comparison study. Dogs undergoing unilateral enucleation were randomized to two groups: one received bupivacaine pRB and saline iSB of the same volume, and the other received saline pRB and bupivacaine iSB. The following intraoperative parameters were recorded: heart rate (HR), respiratory rate (RR), end-tidal CO2 (EtCO2 ); systolic, mean, and diastolic arterial blood pressure (SAP, MAP, and DAP respectively); inspired end-tidal isoflurane concentration (EtISOIns), and expired end-tidal isoflurane concentration (EtISOExp). Pain scores were recorded pre- and postoperatively. Analgesic rescue was documented. Surgical hemorrhage and postoperative bruising and swelling were graded subjectively by the surgeon (HDW) and study coordinator (AEZ). RESULTS: A significant (P = .0399) increase from baseline in overall mean heart rate was recorded in iSB bupivacaine patients (n = 11) compared with pRB bupivacaine patients (n = 11), with no significant differences in other intraoperative physiologic parameters, or pain scores. More analgesic rescue events occurred in iSB bupivacaine patients compared to pRB bupivacaine patients. A near-significant increase in intraoperative bleeding (P = .0519), and a significant increase in bruising (P = .0382) and swelling (P = .0223) was noted in the iSB bupivacaine group. CONCLUSIONS: Preoperative retrobulbar block bupivacaine is more effective than an iSB bupivacaine at controlling both intraoperative and postoperative nociception in dogs undergoing enucleation. Additionally, iSB causes more postoperative bruising and swelling and may be associated with increased intraoperative hemorrhage.

Pet Dogs with Subclinical Acute Radiodermatitis Experience Widespread Somatosensory Sensitization.

Radiation-induced dermatitis (RID) is a common and painful complication of radiotherapy. When severe, radiation-associated pain (RAP) can reduce the efficacy of radiotherapy by limiting the radiation dose given, and/or necessitating breaks in treatment. Current RAP mitigation strategies are of limited efficacy. Our long-term goal is to develop a comparative oncology model, in which novel analgesic interventions for RAP can be evaluated. The aim of this study was to validate quantitative end points indicative of RAP in pet dogs with subclinical and low-grade RID. Extremity soft tissue sarcomas were treated with post-operative irradiation (54 Gy in 18 fractions). Visual toxicity scores, questionnaire-based pain instruments and objective algometry [mechanical quantitative sensory testing (mQST)], were evaluated regularly. Breed-matched control populations were also evaluated to address the effect of potential confounders. Skin biopsies from within the irradiated field were collected at baseline and after 24 Gy irradiation, for analysis of pain-related genes using the nanoString nCounter platform. Relative to control populations, mechanical thresholds decreased in irradiated test subjects as the total radiation dose increased, with the most pronounced effect at the irradiated site. This was accompanied by increased mRNA expression of GFRα3, TNFα, TRPV2 and TRPV4. In a separate set of dogs with moderate-to-severe RID, serum concentrations of artemin (the ligand for GFRα3) were elevated relative to controls (P = 0.015). Progressive reduction in mechanical thresholds, both locally and remotely, indicates widespread somatosensory sensitization during radiation treatment. mQST in pet dogs undergoing radiation treatment represents an innovative tool for preclinical evaluation of novel analgesics.

Risk factors associated with progressive myelomalacia in dogs with complete sensorimotor loss following intervertebral disc extrusion: a retrospective case-control study.

BACKGROUND: Progressive myelomalacia (PMM) is a usually fatal complication of acute intervertebral disc extrusion (IVDE) in dogs but its risk factors are poorly understood. The objective of this retrospective case-control study was to identify risk factors for PMM by comparing dogs with complete sensorimotor loss following IVDE that did and did not develop the disease after surgery. We also investigated whether any risk factors for PMM influenced return of ambulation. Medical records of client-owned dogs with paraplegia and loss of pain perception that underwent surgery for IVDE from 1998 to 2016, were reviewed. Dogs were categorized as PMM yes or no based on clinical progression or histopathology. Walking outcome at 6 months was established. Signalment, onset and duration of signs (categorized), steroids, non-steroidal anti-inflammatory drugs (yes or no), site of IVDE (lumbar intumescence or thoracolumbar) and longitudinal extent of IVDE were retrieved and their associations with PMM and walking outcome were examined using logistic regression. RESULTS: One hundred and ninety seven dogs were included, 45 with and 152 without PMM. A 6-month-outcome was available in 178 dogs (all 45 PMM dogs and 133 control dogs); 86 recovered walking (all in the control group). Disc extrusions at the lumbar intumescence were associated with PMM (p = 0.01, OR: 3.02, CI: 1.3-7.2). Surgery performed more than 12 h after loss of ambulation was associated with PMM (OR = 3.4; CI = 1.1-10.5, p = 0.03 for 12-24 h and OR = 4.6; CI = 1.3-16.6, p = 0.02 for the > 24 h categories when compared with the ≤12 h category). Treatment with corticosteroids was negatively associated with PMM (OR: 3.1; CI: 1.3-7.6, p = 0.01). The only variable to affect walking outcome was longitudinal extent of IVDE (OR = 2.6; CI = 1.3-5.3, p = 0.006). CONCLUSION: Dogs with lumbar intumescence IVDE are at increased risk of PMM. Timing of surgery and corticosteroid use warrant further investigations. PMM and recovery of walking are influenced by different factors.

Tissue-specific changes in size and shape of the ligaments and tendons of the porcine knee during post-natal growth.

Prior studies have analyzed growth of musculoskeletal tissues between species or across body segments; however, little research has assessed the differences in similar tissues within a single joint. Here we studied changes in the length and cross-sectional area of four ligaments and tendons, (anterior cruciate ligament, patellar tendon, medial collateral ligament, lateral collateral ligament) in the tibiofemoral joint of female Yorkshire pigs through high-field magnetic resonance imaging throughout growth. Tissue lengths increased by 4- to 5-fold from birth to late adolescence across the tissues while tissue cross-sectional area increased by 10-20-fold. The anterior cruciate ligament and lateral collateral ligament showed allometric growth favoring change in length over change in cross-sectional area while the patellar tendon and medial collateral ligament grow in an isometric manner. Additionally, changes in the length and cross-sectional area of the anterior cruciate ligament did not increase as much as in the other ligaments and tendon of interest. Overall, these findings suggest that musculoskeletal soft tissue morphometry can vary within tissues of similar structure and within a single joint during post-natal growth.

Lipid and Cholesterol Homeostasis after Arsenic Exposure and Antibiotic Treatment in Mice: Potential Role of the Microbiota.

BACKGROUND: Arsenic-induced liver X receptor/retinoid X receptor (LXR/RXR) signaling inhibition is a potential mechanism underlying the cardiovascular effects caused by arsenic. The gut microbiota can influence arsenic toxic effects. OBJECTIVE: We aimed to explore whether gut microbiota play a role in arsenic-induced LXR/RXR signaling inhibition and the subsequent lipid and cholesterol dysbiosis. METHODS: Conventional and antibiotic-treated mice (AB-treated mice) were exposed to 0.25 ppm and 1 ppm arsenic for 2 wk. Hepatic mRNAs were extracted and sequenced. The expression levels of genes associated with LXR/RXR signaling were quantified by quantitative real-time polymerase chain reaction (qPCR), and serum and hepatic cholesterol levels were measured. Liquid chromatography-mass spectrometry (LC-MS)-based lipidomics were used to examine serum and hepatic lipids. RESULTS: Pathway analysis indicated that arsenic exposure differentially influenced the hepatic signaling pathways in conventional and AB-treated mice. The expression of sterol regulatory element-binding protein 1 (Srebp1c), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), and cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), as well as cholesterol efflux genes, including ATP binding cassette subfamily G member 5/8 (Abcg5/8) and cluster of differentiation 36 (Cd36), was lower in arsenic-exposed conventional mice but not in AB-treated mice. Similarly, under arsenic exposure, the hepatic expression of scavenger receptor class B member 1 (Scarb1), which is involved in reverse cholesterol transport (RCT), was lower in conventional mice, but was higher in AB-treated animals compared with controls. Correspondingly, arsenic exposure exerted opposite effects on the serum cholesterol levels in conventional and AB-treated mice, i.e., higher serum cholesterol levels in conventional mice but lower levels in AB-treated mice than in respective controls. Serum lipid levels, especially triglyceride (TG) levels, were higher in conventional mice exposed to 1 ppm arsenic, while arsenic exposure did not significantly affect the serum lipids in AB-treated mice. Liver lipid patterns were also differentially perturbed in a microbiota-dependent manner. CONCLUSIONS: Our results suggest that in mice, the gut microbiota may be a critical factor regulating arsenic-induced LXR/RXR signaling perturbation, suggesting that modulation of the gut microbiota might be an intervention strategy to reduce the toxic effects of arsenic on lipid and cholesterol homeostasis. https://doi.org/10.1289/EHP4415.

Towards Mass Spectrometry-Based Chemical Exposome: Current Approaches, Challenges, and Future Directions.

The proposal of the "exposome" concept represents a shift of the research paradigm in studying exposure-disease relationships from an isolated and partial way to a systematic and agnostic approach. Nevertheless, exposome implementation is facing a variety of challenges including measurement techniques and data analysis. Here we focus on the chemical exposome, which refers to the mixtures of chemical pollutants people are exposed to from embryo onwards. We review the current chemical exposome measurement approaches with a focus on those based on the mass spectrometry. We further explore the strategies in implementing the concept of chemical exposome and discuss the available chemical exposome studies. Early progresses in the chemical exposome research are outlined, and major challenges are highlighted. In conclusion, efforts towards chemical exposome have only uncovered the tip of the iceberg, and further advancement in measurement techniques, computational tools, high-throughput data analysis, and standardization may allow more exciting discoveries concerning the role of exposome in human health and disease.