Association of Lipoprotein(a) with peri-coronary inflammation in persons with and without HIV infection.

BACKGROUND: Persons with human immunodeficiency virus (HIV) (PWH) have an increased risk of developing cardiovascular disease (CVD) compared to persons without HIV (PWoH). Lipoprotein(a) [Lp(a)] is a known atherosclerotic risk factor in PWoH, but there are no studies investigating Lp(a) and peri-coronary inflammation. OBJECTIVE: To investigate whether Lp(a) is associated with peri-coronary inflammation as assessed by the fat attenuation index (FAI) and activated monocytes and T lymphocytes in PWH and PWoH. METHODS: We measured plasma levels of Lp(a) at study entry in 58 PWH and 21 PWoH without CVD and who had FAI measurements. Associations of Lp(a) with FAI values of the right coronary artery (RCA) and left anterior descending artery were evaluated using multivariable regression models adjusted for potential confounders. Correlations between Lp(a) levels and systemic inflammatory markers and immune cell subsets were examined. RESULTS: Lp(a) was associated with greater peri-coronary inflammation among PWH compared to PWoH (ß=1.73, P=0.019) in the RCA, in adjusted models. Significant correlations were observed with certain inflammatory markers (tumor necrosis factor receptor [TNFR]-I, b=0.295, P<0.001; TNFR-II, b=0.270, P=0.002; high-sensitivity C-reactive protein, b=0.195, P=0.028). Significant correlations were found between Lp(a) levels and several markers of monocyte activation: CD16 -CD163+ (b= -0.199, P=0.024), and CD16 -DR+ MFI (b= -0.179, P=0.042) and T cell subset CD38+CD4+ TEMRA (b= 0.177, P= 0.044). CONCLUSIONS: Lp(a) was associated with greater peri-coronary inflammation in the RCA in PWH compared to PWoH, as well as with select systemic inflammatory markers and specific subsets of immune cells in peripheral circulation.

Association of Soluble Markers of Inflammation With Peri-coronary Artery Inflammation in People With and Without HIV Infection and Without Cardiovascular Disease.

Background: Inflammation is linked to elevated cardiovascular disease (CVD) risk in people with HIV (PWH) on antiretroviral therapy (ART). Fat attenuation index (FAI) is a measure of peri-coronary inflammation that independently predicts CVD risk in HIV-uninfected persons. Whether FAI is associated with soluble inflammatory markers is unknown. Methods: Plasma levels of inflammatory markers were measured in 58 PWH and 16 controls without current symptoms or prior known CVD who underwent coronary computed tomography angiography and had FAI measurements. A cross-sectional analysis was performed, and associations of markers with FAI values of the right coronary artery (RCA) and left anterior descending artery (LAD) were assessed using multivariable regression models adjusted for the potential confounders age, sex, race, low-density lipoprotein cholesterol, body mass index, and use of lipid-lowering medication. Results: Several inflammatory markers had significant associations with RCA or LAD FAI in adjusted models, including sCD14, sCD163, TNFR-I, and TNFR-II, CCL5, CX3CL1, IP-10. Conclusions: The associations between indices of systemic and peri-coronary inflammation are novel and suggest that these systemic markers and FAI together are promising noninvasive biomarkers that can be applied to assess asymptomatic CVD in people with and without HIV; they also may be useful tools to evaluate effects of anti-inflammatory interventions.

Congenital Malformations Associated With a Single Umbilical Artery in Twin Pregnancies.

A single umbilical artery (SUA) was identified in 1.5% of twin pregnancies. The presence of a SUA in a twin pregnancy was associated with a 50% incidence of fetal anomalies, many of them complex and severe. The embryology and pathophysiological mechanisms associated with a SUA are reviewed. Aneuploidy is relatively common and should be considered, particularly in the presence of associated anomalies. Fetal growth restriction is frequent and preterm delivery is common.

Pregnancy prognosis associated with an isolated single umbilical artery in twin pregnancy.

To determine the prognosis of an isolated single umbilical artery (SUA) in a twin pregnancy, we selected twin pregnancies with a second trimester ultrasound diagnosing a SUA in at least one fetus at our tertiary hospital. This was confirmed by placental histopathology or by expert review of ultrasound images. Cases were identified by searching the hospital ultrasound database over a period of 7.5 years. Higher order multiples or coexistent aneuploidy or major anomalies were excluded. Each case of an isolated SUA was assigned three consecutive twin pregnancy controls paired for chorionicity and maternal age. Primary outcomes were preterm birth <34 weeks, small for gestational age (SGA) or perinatal death. Other outcomes included antenatal growth restriction, mode of delivery, and admission to neonatal intensive care or special care nursery. Nine pregnancies (18 fetuses) were identified for analysis as cases. Isolated SUA was associated with preterm birth <34 weeks (odds ratio = 12.2; 95% CI = 2.0-75.2; p = .005) but not for SGA. There was also no difference in SGA between the affected twin and its normal co-twin. Perinatal death was increased but after controlling for gestational age and clustering this finding was no longer significant. We conclude that isolated SUA in twins adds a degree of risk to an already high-risk pregnancy but does not increase the need for surveillance for growth restriction.

Resolution of airflow obstruction on polysomnography after laryngotracheal reconstruction with anterior tracheal wall suspension in a patient with DiGeorge Syndrome.

DiGeorge Syndrome (DGS) may be associated with airway abnormalities including laryngomalacia and suprastomal collapse of the trachea (SCT), which may lead to sleep disordered breathing (SDB). We present a 4-year-old boy with DGS, SCT, and SDB by polysomnography (PSG) while the tracheostomy tube was capped. The patient underwent anterior tracheal wall suspension (ATWS) with concurrent tracheostomy decannulation. Following the repair, the patient experienced improved airway patency visually and by PSG with resolution of obstructive sleep apnea and hypoventilation. ATWS is an effective method to repair SCT in selected patients and may lead to early decannulation and improvement of SDB.

Sleep disordered breathing in children with mitochondrial disease.

A retrospective chart review study was performed to determine the presence of sleep disordered breathing (SDB) in children with primary mitochondrial disease (MD). The symptoms, sleep-related breathing, and movement abnormalities are described for 18 subjects (ages 1.5 to 18 years, 61% male) with MD who underwent polysomnography in our pediatric sleep center from 2007 to 2012. Of the 18 subjects with MD, the common indications for polysomnography were excessive somnolence or fatigue (61%, N = 11), snoring (44%, N = 8), and sleep movement complaints (17%, N = 3). Polysomnographic measurements showed SDB in 56% (N = 10) (obstructive sleep apnea in 60% (N = 6), hypoxemia in 40% (N = 4), and sleep hypoventilation in 20% (N = 2)). There was a significant association between decreased muscle tone and SDB (P: 0.043) as well as obese and overweight status with SDB (P = 0.036). SDB is common in subjects with MD. Early detection of SDB, utilizing polysomnography, should be considered to assist in identification of MD patients who may benefit from sleep-related interventions.

Unique small RNA signatures uncovered in the tammar wallaby genome.

BACKGROUND: Small RNAs have proven to be essential regulatory molecules encoded within eukaryotic genomes. These short RNAs participate in a diverse array of cellular processes including gene regulation, chromatin dynamics and genome defense. The tammar wallaby, a marsupial mammal, is a powerful comparative model for studying the evolution of regulatory networks. As part of the genome sequencing initiative for the tammar, we have explored the evolution of each of the major classes of mammalian small RNAs in an Australian marsupial for the first time, including the first genome-scale analysis of the newest class of small RNAs, centromere repeat associated short interacting RNAs (crasiRNAs). RESULTS: Using next generation sequencing, we have characterized the major classes of small RNAs, micro (mi) RNAs, piwi interacting (pi) RNAs, and the centromere repeat associated short interacting (crasi) RNAs in the tammar. We examined each of these small RNA classes with respect to the newly assembled tammar wallaby genome for gene and repeat features, salient features that define their canonical sequences, and the constitution of both highly conserved and species-specific members. Using a combination of miRNA hairpin predictions and co-mapping with miRBase entries, we identified a highly conserved cluster of miRNA genes on the X chromosome in the tammar and a total of 94 other predicted miRNA producing genes. Mapping all miRNAs to the tammar genome and comparing target genes among tammar, mouse and human, we identified 163 conserved target genes. An additional nine genes were identified in tammar that do not have an orthologous miRNA target in human and likely represent novel miRNA-regulated genes in the tammar. A survey of the tammar gonadal piRNAs shows that these small RNAs are enriched in retroelements and carry members from both marsupial and tammar-specific repeat classes. Lastly, this study includes the first in-depth analyses of the newly discovered crasiRNAs. These small RNAs are derived largely from centromere-enriched retroelements, including a novel SINE. CONCLUSIONS: This study encompasses the first analyses of the major classes of small RNAs for the newly completed tammar genome, validates preliminary annotations using deep sequencing and computational approaches, and provides a foundation for future work on tammar-specific as well as conserved, but previously unknown small RNA progenitors and targets identified herein. The characterization of new miRNA target genes and a unique profile for crasiRNAs has allowed for insight into multiple RNA mediated processes in the tammar, including gene regulation, species incompatibilities, centromere and chromosome function.

Pericentric and centromeric transcription: a perfect balance required.

The pericentromere and centromere regions of the genome have previously been considered tightly compacted and transcriptionally inert. However, there is mounting evidence that these regions not only actively produce transcripts but that these pericentric and centromeric transcripts are also vital to maintaining genome stability and proper cell division. In this review, we define the pericentromere and centromere of eukaryotic chromosomes in terms of their histone modifications and their nascent transcripts. In addition, we present the currently known roles these transcripts play in heterochromatin formation, development, and differentiation, as well as their interaction with centromeric proteins, and ultimately centromere function. Recent work has added considerable complexity to the theoretical framework defining the innate requirement for pericentric and centromeric transcription. It is clear that maintaining a fine balance of transcriptional output is critical, as deviations from this balance result in centromere disfunction and genomic instability.

Acute compartment syndrome of the forearm.

BACKGROUND: The aims of this study were to document our experience with acute forearm compartment syndrome and to determine the risk factors for the need for split-thickness skin-grafting and the development of complications after fasciotomy. METHODS: We identified from our trauma database all patients who underwent fasciotomy for an acute forearm compartment syndrome over a twenty-two-year period. Diagnosis was made with use of clinical signs in all patients, with compartment pressure monitoring used as a diagnostic adjunct in some patients. Outcome measures were the use of split-thickness skin grafts and the identification of complications following forearm fasciotomy. RESULTS: There were ninety patients in the study cohort, with a mean age of thirty-three years (range, thirteen to eighty-one years) and a significant male predominance (eighty-two patients; p < 0.001). A fracture of the radius or ulna, or both, was seen in sixty-two patients (69%), with soft-tissue injuries as the causative factor in twenty-eight (31%). The median time to fasciotomy was twelve hours (range, two to seventy-two hours). Risk factors for requiring split-thickness skin-grafting were younger age and a crush injury (p < 0.05 for both). Risk factors for the development of complications were a delay in fasciotomy of more than six hours (p = 0.018) and preoperative motor symptoms, which approached significance (p = 0.068). CONCLUSIONS: Forearm compartment syndrome requiring fasciotomy predominantly affects males and can occur following either a fracture or soft-tissue injury. Age is an important predictor of undergoing split-thickness skin-grafting for wound closure. Complications occur in a third of patients and are associated with an increasing time from injury to fasciotomy.

Effects of depleted uranium on survival, growth, and metamorphosis in the African clawed frog (Xenopus laevis).

Embryos (stage 8-47, Nieuwkoop and Faber) of the African clawed frog (Xenopus laevis) were subjected to water-borne depleted uranium (DU) concentrations that ranged from 4.8 to 77.7 mg/L using an acute 96-h frog embryo teratogenesis assay-Xenopus (FETAX). In a chronic 64-d assay, X. laevis (from embryo through metamorphosis; stages 8-66) were subjected to concentrations of DU that ranged from 6.2 to 54.3 mg/L. Our results indicate DU is a non teratogenic metal. No effects on mortality, malformations, or growth were observed in the 96-h FETAX with concentrations of DU that ranged from 4.8 to 77.7 mg/L. From stage 8 to stage 47, X. laevis tadpoles do not actively feed and the gills are not well developed. Thus, uptake of DU was reduced despite exposure to elevated concentrations. The 64-d assay resulted in no concentration response for either mortality or malformations; however, a delay in metamorphosis was observed in tadpoles subjected to elevated DU concentrations (from 13.1 to 54.3 mg/L) compared to tadpoles in both the well-water control and reference. The delay in metamorphosis was likely due to increasing body burden of DU that ranged from 0.98 to 2.82 mg/kg.