Septal Volume Research Articles

Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung.

Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive, and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as intervention strategies. C57BL/6N mice fed control diet (10% fat) or high-fat diet (HFD; 60% fat) were left untreated or were supplemented with 3 mM spermidine, had access to running wheels for voluntary activity, or a combination of both. After 30 wk, lung mechanics was assessed, and left lungs were analyzed by design-based stereology. HFD exerted minor effects on lung mechanics and resulted in higher body weight and elevated lung, air, and septal volumes. The number of alveoli was higher in HFD-fed animals. This was accompanied by an increase in epithelial, but not endothelial, surface area. Moreover, air-blood barrier and endothelium were significantly thicker. Neither treatment affected HFD-related body weights. Spermidine lowered lung volumes as well as endothelial and air-blood barrier thicknesses toward control levels and substantially increased the endothelial surface area under HFD. Activity resulted in decreased volumes of lung, septa, and septal compartments but did not affect vascular changes in HFD-fed mice. The combination treatment showed no additive effect. In conclusion, excess fat consumption induced alveolar capillary remodeling indicative of impaired perfusion and gas diffusion. Spermidine alleviated obesity-related endothelial alterations, indicating a beneficial effect, whereas physical activity reduced lung volumes apparently by other, possibly systemic effects.

Rare Disease: Cardiac Risk Assessment With MRI in Patients With Myotonic Dystrophy Type 1.

Introduction: To evaluate myocardial strain and extracellular volume in myotonic dystrophy type 1 (DM1) patients as potential imaging biomarkers of subclinical cardiac pathology.Materials and methods: We retrospectively analyzed 9 DM1 patients without apparent cardiac disease who had undergone cardiac magnetic resonance at our center. Patients were age- and sex-matched with healthy controls. The Mann-Whitney U test was used to compare cardiac strain between the two groups. The t-test was used to compare the extracellular volume obtained in DM1 patients with that in healthy subject. Spearman's ρ was used for studying the associations among imaging parameters.Results: Global cardiac strain (median −19.1%; IQR −20.5%, −16.5%) in DM1 patients was lower (p = 0.011) than that in controls (median−21.7%; IQR−22.7%,-21.3%). Global extracellular volume in DM1 patients (median 32.3%; IQR 29.3%,36.8%) was significantly (p = 0.008) higher than that reported in literature in healthy subjects (median 25.6%; IQR 19.9%,31.9%). Global cardiac strain showed a strong, positive correlation with septal strain (ρ = 0.767, p = 0.016) and with both global (ρ = 0.733 p = 0.025) and septal extracellular volume (ρ = 0.767, p = 0.016).Discussion: The increase in cardiac extracellular volume and decrease in strain are signs of early cardiac pathology in DM1. Physicians dealing with DM1 may take into consideration cardiac magnetic resonance as a screening tool to identify early cardiac involvement in this condition.

Study of the Vascularity of Uterine Septum Using Three Dimensional Power Doppler Ultrasound

Abstract Background Uterine anomalies are a relatively common congenital abnormality, with uterine septum being the most common. This is even truer in patients with recurrent pregnancy loss, in whom rates of uterine abnormalities may approach 15% to 27%. Historically, the uterine septum has been approached via laparotomy through either a Tompkins or Jones procedure. These successful, but highly morbid, procedures require laparotomy with significant hospital stays, subsequent cesarean delivery, and have carried a high risk of adhesion formation. More recently, this surgery has been supplanted by hysteroscopy or other minimally invasive methodologies. Objective To assess the relation between the vascularity of uterine septum and obstetric performance with Transvaginal 3D Power Doppler Ultrasound. Patients and Methods Early Cancer Detection Unit and Ultrasound and Fetal special care Unit in Ain Shams University Maternity Hospital (ASUMH). Recruitment took place between May 2017 and November 2018. Cross-sectional study. The study included 30 cases of women with uterine septum. Intervention: Transvaginal 3D power Doppler ultrasound was done to all cases with septal volume and vascularity assessment using VOCAL system and Histogram facility. The study included 30 patients with septate uterus, twelve of them suffered from 1ry infertility while the other eighteen suffered from recurrent abortion. Results There was statistical significant difference between the two groups regarding vascularity (VI, FI, and VFI) of septum (P < 0.05). Conclusion The vascularity of septate uterus is variable. The power Doppler indices shows that septate uterus in cases with recurrent abortion is highly vascular while in cases with 1ry infertility shows low vascularity. Highly vascular septum may be a site of implantation which may be a cause of recurrent abortion thus; excision of the septum may help prevent recurrent abortion, while low vascular septum may prevent implantation which may be a cause of infertility thus; incision of the septum may help in treatment of infertility. Correlation with histopathologic features of septum may be required to decide the best management of the septum.

Lack of impact of radiologic septal measurements upon patient symptoms and performance of septoplasty during endoscopic sinus surgery.

Recent literature suggests that concurrent septoplasty during endoscopic sinus surgery (ESS) improves patient outcomes, however, the underlying indications for performing concurrent septoplasty are unknown. The objective of this study was to investigate the relationship between objective radiologic measures of nasal septal deviation with preoperative patient symptomatology and measures of CRS disease severity. We also sought to understand the association of objective radiologic measurements with surgeon performance of concurrent septoplasty during ESS. Seventy-four patients with CRS undergoing ESS were prospectively enrolled. Angles of septal deviation, intranasal areas and volumes were assessed on preoperative computed tomography (CT) scans and correlated with a robust battery of patient reported outcomes measures (PROMs), objective measures of CRS severity including olfaction scores, radiologic and endoscopic staging, and performance of septoplasty. Intranasal areas and volumes demonstrated only weak linear associations with patient-reported nasal congestion, however, angles of septal deviation alone did not correlate with congestion or any other PROM measure. Meanwhile, radiologic septal-related measurements did not correlate with objective measures of CRS disease severity or the performance of a concurrent septoplasty. Though prior studies demonstrate improved patient outcomes in the setting of concurrent septoplasty during ESS, this study failed to establish an association between preoperative radiologic septal-related measurements and patient symptomatology or surgeon decision to perform septoplasty. Although objective factors to identify patients most likely to benefit from concurrent septoplasty remain unidentified, the potential improvement of surgical recommendations and patient outcomes makes this an important area of continued investigation.

No increased extracellular volume fraction or conduction time after childhood septal myectomy.

The aim of this study was to assess the effect of surgical septal myectomy performed during early childhood for severe, drug-refractory hypertrophic cardiomyopathy with left ventricular outflow tract obstruction on the extent of septal myocardial extracellular volume fraction and the potential risk of developing atrioventricular cardiac conduction system disease. In this retrospective study, data from 30 patients with a confirmed diagnosis of childhood-onset hypertrophic cardiomyopathy were reviewed including cardiovascular magnetic resonance (CMR) with myocardial T1 mapping and late gadolinium enhancement, histopathology of myocardial specimens, transthoracic echocardiography, electrocardiography, 24-h Holter and cardiopulmonary exercise testing. Eighteen patients without were compared to 12 patients with prior septal myectomy performed during childhood (non-operated versus myectomy patients). Late gadolinium enhancement on CMR as a correlate for focal myocardial fibrosis was found in 53% of patients, predominantly located in the septal region, with no difference between groups. As compared to non-operated patients, those after myectomy showed a similar amount of total and septal extracellular volume fraction, as calculated from pre- and post-contrast CMR T1 mapping, which is a correlate for diffuse interstitial myocardial fibrosis. PQ-intervals or the occurrence of higher degree conduction system disease were equal between the 2 groups. Data from CMR and electrocardiography suggest that surgical septal myectomy performed during early childhood for severe obstructive hypertrophic cardiomyopathy does not cause an increased septal extracellular volume fraction or delayed atrioventricular conduction time on long-term follow-up.

Age-Related Structural and Functional Changes in the Mouse Lung.

Lung function declines with advancing age. To improve our understanding of the structure-function relationships leading to this decline, we investigated structural alterations in the lung and their impact on micromechanics and lung function in the aging mouse. Lung function analysis was performed in 3, 6, 12, 18, and 24 months old C57BL/6 mice (n = 7–8/age), followed by lung fixation and stereological sample preparation. Lung parenchymal volume, total, ductal and alveolar airspace volume, alveolar volume and number, septal volume, septal surface area and thickness were quantified by stereology as well as surfactant producing alveolar epithelial type II (ATII) cell volume and number. Parenchymal volume, total and ductal airspace volume increased in old (18 and 24 months) compared with middle-aged (6 and 12 months) and young (3 months) mice. While the alveolar number decreased from young (7.5 × 106) to middle-aged (6 × 106) and increased again in old (9 × 106) mice, the mean alveolar volume and mean septal surface area per alveolus conversely first increased in middle-aged and then declined in old mice. The ATII cell number increased from middle-aged (8.8 × 106) to old (11.8 × 106) mice, along with the alveolar number, resulting in a constant ratio of ATII cells per alveolus in all age groups (1.4 ATII cells per alveolus). Lung compliance and inspiratory capacity increased, whereas tissue elastance and tissue resistance decreased with age, showing greatest changes between young and middle-aged mice. In conclusion, alveolar size declined significantly in old mice concomitant with a widening of alveolar ducts and late alveolarization. These changes may partly explain the functional alterations during aging. Interestingly, despite age-related lung remodeling, the number of ATII cells per alveolus showed a tightly controlled relation in all age groups.

Left ventricular structural and functional changes in Friedreich ataxia - Relationship with body size, sex, age and genetic severity.

IntroductionAlthough a concentric pattern of left ventricular (LV) geometry appears to be common in Friedreich ataxia (FRDA), there is no accepted method for diagnosing LV abnormalities in FRDA, sex and body size have often not been taken into consideration, and it has not been clear whether children and adults should be classified using the same criteria. The aim of this study was to better define the LV geometric changes in FRDA with respect to sex, body size and subject age, and to investigate the relationship of LV changes with genetic severity, as assessed by GAA repeat length within the shorter allele of the FXN gene (GAA1).MethodsEchocardiography was performed in 216 subjects (68 children, 148 adults), measurements were made at end-diastole of LV internal diameter (LVEDID), septal wall thickness (SWT), LV length (LVEDL) and LV volume (LVEDV), and calculations were made of relative wall thickness (RWT), LV mass and LV ejection fraction (LVEF).ResultsThe most common LV abnormalities in both adults and children with FRDA were increases in RWT and age-normalized RWT. In adults with a normal LVEF, all LV variables other than RWT were larger in males independent of body surface area (BSA), and all LV variables other than SWT and RWT were positively correlated with BSA. After adjustment for sex and BSA, GAA1 was a positive correlate of SWT and RWT (but not of LV mass), and was an inverse correlate of LVEDID, LVEDL and LVEDV. In children with a normal LVEF, SWT, LV mass and LVEDL were larger in males than females after adjusting for BSA, and in combination with sex, BSA was a positive correlate of all the LV variables except SWT and RWT. In children there were no correlations of GAA1 with any of the LV variables.ConclusionIn FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.

Postnatal morphological lung development of wild type and CD26/DPP4 deficient rat pups in dependency of LPS exposure

BackgroundRodents are born with morphological immature lungs and an intact surfactant system. CD26/DPP4 is a multifactorial transmembrane integral type II protein, which is involved in physiological and pathophysiological processes and is already expressed during development. CD26/DPP4, called CD26 in the following, is able to enhance or dampen differently triggered inflammation. LPS exposure often used to simulate perinatal infection delays lung development. ObjectiveA perinatal LPS rat model was used to test the hypothesis that CD26 deficiency modulates LPS-induced retardation in morphological lung development. MethodsNew born Fischer CD26 positive (CD26+) and deficient (CD26−) rats were exposed to LPS on postnatal day (day post partum, dpp) 3 and 5. Morphological parameters of lung development were determined stereologically. Lung development was analysed in 7, 10 14 and 21day old rats. ResultsCompared to controls LPS application resulted (1) in a mild inflammation independent of the strain, (2) in significantly lower total surface and volume of alveolar septa combined with significantly higher total volume of airspaces and alveolar size on dpp 7 in both substrains. However, compared to controls in LPS treated CD26− rats significant lower values of total septal surface and volume combined with higher values of total parenchymal airspaces and alveolar size were found until the end of classical alveolarization (dpp14). In LPS treated CD26+ rat pups the retardation was abolished already on dpp 10. ConclusionIn absence of CD26, LPS enhances the delay of morphological lung development. Morphological recovery was slower after the end of LPS exposure in CD26 deficient lungs.

Voluntary Activity Modulates Sugar-Induced Elastic Fiber Remodeling in the Alveolar Region of the Mouse Lung.

Diabetes and respiratory diseases are frequently comorbid conditions. However, the mechanistic links between hyperglycemia and lung dysfunction are not entirely understood. This study examined the effects of high sucrose intake on lung mechanics and alveolar septal composition and tested voluntary activity as an intervention strategy. C57BL/6N mice were fed a control diet (CD, 7% sucrose) or a high sucrose diet (HSD, 35% sucrose). Some animals had access to running wheels (voluntary active; CD-A, HSD-A). After 30 weeks, lung mechanics were assessed, left lungs were used for stereological analysis and right lungs for protein expression measurement. HSD resulted in hyperglycemia and higher static compliance compared to CD. Lung and septal volumes were increased and the septal ratio of elastic-to-collagen fibers was decreased despite normal alveolar epithelial volumes. Elastic fibers appeared more loosely arranged accompanied by an increase in elastin protein expression. Voluntary activity prevented hyperglycemia in HSD-fed mice. The parenchymal airspace volume, but not the septal volume, was increased. The septal extracellular matrix (ECM) composition together with the protein expression of ECM components was similar to control levels in the HSD-A-group. In conclusion, HSD was associated with elastic fiber remodeling and reduced pulmonary elasticity. Voluntary activity alleviated HSD-induced ECM alterations, possibly by preventing hyperglycemia.

Erythropoietin inhalation enhances adult canine alveolar-capillary formation following pneumonectomy.

Paracrine erythropoietin (EPO) signaling in the lung recruits endothelial progenitor cells, promotes cell maturation and angiogenesis, and is upregulated during canine postpneumonectomy (PNX) compensatory lung growth. To determine whether inhalational delivery of exogenous EPO augments endogenous post-PNX lung growth, adult canines underwent right PNX and received, via a permanent tracheal stoma, weekly nebulization of recombinant human EPO-containing nanoparticles or empty nanoparticles (control) for 16 wk. Lung function was assessed under anesthesia pre- and post-PNX. The remaining lobes were fixed for detailed morphometric analysis. Compared with control treatment, EPO delivery significantly increased serum EPO concentration without altering systemic hematocrit or hemoglobin concentration and abrogated post-PNX lipid oxidative stress damage. EPO delivery modestly increased post-PNX volume densities of the alveolar septum per unit of lung volume and type II epithelium and endothelium per unit of septal tissue volume in selected lobes. EPO delivery also augmented the post-PNX increase in alveolar double-capillary profiles, a marker of intussusceptive capillary formation, in all remaining lobes. EPO treatment did not significantly alter absolute resting lung volumes, lung and membrane diffusing capacities, alveolar-capillary blood volume, pulmonary blood flow, lung compliance, or extravascular alveolar tissue volumes or surface areas. Results established the feasibility of chronic inhalational delivery of growth-modifying biologics in a large animal model. Exogenous EPO selectively enhanced cytoprotection and alveolar angiogenesis in remaining lobes but not whole-lung extravascular tissue growth or resting function; the nonuniform response contributes to structure-function discrepancy, a major challenge for interventions aimed at amplifying the innate potential for compensatory lung growth.

Advanced Imaging to Phenotype Patients With a Systemic Right Ventricle.

BackgroundReduced ventricular function and decreased exercise capacity are widespread in adults with complete transposition of the great arteries after atrial switch (TGA‐Mustard/Senning) and congenitally corrected TGA (ccTGA). Advanced imaging techniques may help to better phenotype these patients and evaluate exercise cardiac response.Methods and ResultsThirty‐three adults with a systemic right ventricle (70% TGA‐Mustard/Senning, 37±9 years of age, 24% female, 94% New York Heart Association class I‐II) underwent echocardiogram, cardiopulmonary exercise testing, and cardiovascular magnetic resonance imaging at rest and during a 4‐stage free‐breathing bicycle test. They were compared with 12 healthy controls (39±10 years of age, 25% female, all New York Heart Association class I). TGA‐Mustard/Senning patients had a higher global circumferential strain (−15.8±3.6 versus −11.2±5.2%, P=0.008) when compared with ccTGA, whereas global longitudinal strain and systemic right ventricle contractility during exercise were similar in both groups. Septal extracellular volume (ECV) in ccTGA was significantly higher than in TGA‐Mustard/Senning (30.2±2.0 versus 27.1±2.7%, P=0.005). During exercise, TGA‐Mustard/Senning had a fall in end‐diastolic volume and stroke volume (11% and 8%, respectively; both P≤0.002), whereas ccTGA could increase their stroke volume in the same way as healthy controls. Because of a greater heart rate reserve in TGA‐Mustard/Senning (P for interaction=0.010), cardiac index and peak oxygen uptake were similar between both patient groups.ConclusionsCaution should be exercised when evaluating pooled analyses of systemic right ventricle patients, given the differences in myocardial contraction pattern, septal extracellular volume, and the exercise response of TGA‐Mustard/Senning versus ccTGA patients. Longitudinal follow‐up will determine whether abnormal exercise cardiac response is a marker of earlier failure.

Effects of Different Heart Dimensions on Race Performance in Thorougbred Race Horses

Background: Athletic superiority could be present in horses with a specific cardiac phenotype that differs between race types. Measurement of chamber dimensions is considered one of the most important tools for assessing heart disease severity and prognosis as well as for evaluating cardiac responses to training and detraining. The purpose of this study was to evaluate the changes of cardiac dimensions and pathological finding in intensive exercise of Thoroughbred horses on their race performance by using the 2-D Doppler and M-Mode echocardiography according to their age, body weight and sex.Materials, Methods & Results: Thoroughbred horses (40 females and 40 males) in the facilities, Ankara and Istanbul of Racetract, of Jockey Club of Turkey were included in the study. Horses were assigned as 4 study groups according to their ages and body weight separately. Group IV and I non-race horses were >7 year-old and >490 kg, >1 to ≤2 and ≤ 390 kg, Group II and III race horses were >2 to ≤3 and >390 kg to ≤ 440 kg, >3 to ≤6 year-old and >440 kg to ≤490 kg, respectively. Intensive exercise was applied to horses except group IV. The relationships between selected echocardiographic variables according to horse age, body weight and sex were analysed. Specifically left ventricle (LV) assessment by diameter in systole and diastole (LVDd and LVDs) and posterior wall thickness (LVWs and LVWd), interventricular septal thickness (IVSd and IVSs), ejection fraction (EF), fractional shortening (FS), Stroke Volume (SV), cardiac output (CO) and left ventricle mass (LVM) were determined. Descriptive statistical analyses, including mean and standard deviation were used to summarise the data. Significant differences of LVDd (P < 0.001), LVDs (P < 0.001) and SV (P < 0.001) were only determined in group I compared to group IV non-race horses. Significant differences in values of CO (P < 0.001) was determined in group III compared to group II race horses, which shows the eccentric left ventricle hypertrophy developed in Thoroughbred horses during years of racing, especially more than 4 years old of intensive exercise. Present study indicated that linear relationships between echocardiographic variables and age (P < 0.001) and body weight (P < 0.001) were found, with the linear relationships between echocardiographic variables and age being stronger than those with body weight.Discussion: Relationships between echocardiographic measurements and body weight (BW) seem to be stronger than those with age. In horses, the effects of training and growth on echocardiographic measurements have been documented, and the influence of breed has been suggested by several authors. Also, it has been demonstrated that an eccentric cardiac hypertrophy occurs in response to race training attributable to an increased diastolic stress and thus, higher heart chambers are expected in the trained Thoroughbreds and Standardbreds horses. The lack of significant differences between age groups in several LV performance indices, such as FS% and EF% might indicate that the values reported here can be extrapolated to Thorougbred horses of different ages and BW. The homogeneity of racehorse management and their closed breeding population should allow unique insights into the subtle differences in cardiac adaptations that might be associated with small differences in training horses for different race disciplines.

Acclimatization of low altitude-bred deer mice ( Peromyscus maniculatus) to high altitude.

A colony of deer mice subspecies ( Peromyscus maniculatus sonoriensis) native to high altitude (HA) has been maintained at sea level for 18-20 generations and remains genetically unchanged. To determine if these animals retain responsiveness to hypoxia, one group (9-11 wk old) was acclimated to HA (3,800 m) for 8 wk. Age-matched control animals were acclimated to a lower altitude (LA; 252 m). Maximal O2 uptake (V̇o2max) was measured at the respective altitudes. On a separate day, lung volume, diffusing capacity for carbon monoxide (DLCO), and pulmonary blood flow were measured under anesthesia using a rebreathing technique at two inspired O2 tensions. The HA-acclimated deer mice maintained a normal V̇o2max relative to LA baseline. Compared with LA control mice, antemortem lung volume was larger in HA mice in a manner dependent on alveolar O2 tension. Systemic hematocrit, pulmonary blood flow, and standardized DLCO did not differ significantly between groups. HA mice showed a higher postmortem alveolar-capillary hematocrit, larger alveolar ducts, and smaller distal conducting structures. In HA mice, absolute volumes of alveolar type I epithelia and endothelia were higher whereas that of interstitia was lower than in LA mice. These structural changes occurred without a net increase in whole-lung septal tissue-capillary volumes or surface areas. Thus, deer mice bred and raised to adulthood at LA retain phenotypic plasticity and adapt to HA without a decrement in V̇o2max via structural (enlarged airspaces, alveolar septal remodeling) and nonstructural (lung expansion under hypoxia) mechanisms and without an increase in systemic hematocrit or compensatory lung growth. NEW & NOTEWORTHY Deer mice ( Peromyscus maniculatus) are robust and very active mammals that are found across the North American continent. They are also highly adaptable to extreme environments. When introduced to high altitude they retain remarkable adaptive ability to the low-oxygen environment via lung expansion and remodeling of existing lung structure, thereby maintaining normal aerobic capacity without generating more red blood cells or additional lung tissue.

Early and late pulmonary effects of nebulized LPS in mice: An acute lung injury model.

Background and objectiveAcute respiratory distress syndrome (ARDS) has a high mortality rate of 35–46% depending on its severity. Animal models are crucial to better understand the pathophysiology of diseases, including ARDS. This study presents a feasible animal model of acute lung injury (ALI) using nebulized lipopolysaccharide (LPS) in a non-invasive approach, focusing on its short and long-term effects.MethodsMice received nebulized LPS or vehicle only (control group). Blood, BALF and lung tissue were collected 24 hours (LPS 24h) or 5 weeks (LPS 5w) after the nebulized LPS-induced lung injury. Inflammatory cytokines were assessed in the blood serum, BALF and lung tissue. Stereological analyses and remodeling changes were assessed by histology and immunohistochemistry at the specified time points.ResultsThe LPS 24h group showed increased pro-inflammatory cytokine levels, intense cell influx, increased total septal volume, septal thickening and decreased surface density of the alveolar septa. The LPS 5w group showed persistent lung inflammation, septal thickening, increased total lung volume, accentuated collagen deposition, especially of collagen type I, and decreased MMP-2 protein expression.ConclusionWe present a feasible, reproducible and non-invasive nebulized-LPS animal model that allows the assessment of both the acute and late phases of acute lung injury. The presence of lung remodeling with collagen deposition after 5 weeks makes it useful to study the pathophysiology, complications, and possible therapeutic intervention studies that aim to understand and reduce pulmonary fibrosis in the late phases of ALI.

Morphological interaction between the nasal septum and nasofacial skeleton during human ontogeny.

The nasal septal cartilage is thought to be a key growth center that contributes to nasofacial skeletal development. Despite the developmental influence of the nasal septum however, humans often exhibit a high frequency of septal deviation suggesting discordance in the growth between the septum and surrounding nasofacial skeleton. While there are numerous etiological factors that contribute to septal deviation, the surrounding nasofacial skeleton may also act to constrain the septum, resulting in altered patterns of growth. That is, while the nasal septum has a direct morphogenetic influence on aspects of the nasofacial skeleton, other nasofacial skeletal components may restrict septal growth resulting in deviation. Detailing the developmental relationship between these structures is important not only for understanding the causal determinants of nasal septal deviation, but also for developing a broader understanding of the complex interaction between the facial skeleton and chondrocranium. We selected 66 non-syndromic subjects from the University of Minnesota Orthodontic Clinic who ranged from 7 to 18years in age and had an existing pretreatment cone-beam computed tomography (CBCT) scan. Using CBCT data, we examined the developmental relationship between nasal septal deviation and the surrounding nasofacial skeleton. We measured septal deviation as a percentage of septal volume relative to a modeled non-deviated septum. We then collected a series of coordinate landmark data in the region immediately surrounding the nasal septum in the midsagittal plane representing the nasofacial skeleton. First, we examined ontogenetic changes in the magnitude of nasal septal deviation relative to chronological age and nasofacial size. Next, using Procrustes-based geometric morphometric techniques, we assessed the morphological relationship between nasal septal deviation and nasofacial skeletal shape. Our results indicate that variation in the magnitude of nasal septal deviation was established in our earliest age group and maintained throughout ontogeny. Moreover, nasal septal deviation was correlated with non-allometric variation in nasofacial shape restricted to the region of the anterior sphenoid body. Ultimately, our results suggest that early developmental variation in midline basicranial components may act to alter or constrain patterns of nasal septal growth.

Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene

The lipid transporter, ATP binding cassette class A3 (ABCA3), plays a critical role in the biogenesis of alveolar type 2 (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with diffuse parenchymal lung disease (DPLD), the most common of which is a missense mutation (valine substitution for lysine at residue 292 (ABCA3E292V)) that leads to functional impairment of the transporter in vitro. The consequences of ABCA3E292V gene expression in vivo are unknown. To address this question, we developed mouse models expressing ABCA3E292V knocked-in to the endogenous mouse locus. The parental (F1) mouse line (mAbca3E292V) that retained an intronic pgk-Neo selection cassette (inserted in reverse orientation) (mAbca3E292V–rNeo) demonstrated an allele dependent extracellular surfactant phospholipid (PL) deficiency. We hypothesize that this PL deficiency leads to aberrant parenchymal remodeling contributing to the pathophysiology of the DPLD phenotype. Compared to wild type littermates, baseline studies of mice homozygous for the pgk-Neo insert (mAbca3E292V–rNeo+/+) revealed nearly 50% reduction in bronchoalveolar lavage (BAL) PL content that was accompanied by quantitative reduction in AT2 LB size with a compensatory increase in LB number. The phenotypic alteration in surfactant lipid homeostasis resulted in an early macrophage predominant alveolitis which peaked at 8 weeks of age. This was followed by age-dependent development of histological DPLD characterized initially by peribronchial inflammatory cell infiltration and culminating in both an emphysema-like phenotype (which included stereologically quantifiable reductions in both alveolar septal surface area and volume of septal wall tissue) plus foci of trichrome-positive collagen deposition together with substantial proliferation of hyperplastic AT2 cells. In addition to spontaneous lung remodeling, mABCA3E292V–rNeo mice were rendered more vulnerable to exogenous injury. Three weeks following intratracheal bleomycin challenge, mAbca3–rNeo mice demonstrated allele-dependent susceptibility to bleomycin including enhanced weight loss, augmented airspace destruction, and increased fibrosis. Removal of the rNeo cassette from mAbca3 alleles resulted in restoration of BAL PL content to wild-type levels and an absence of changes in lung histology up to 32 weeks of age. These results support the importance of surfactant PL homeostasis as a susceptibility factor for both intrinsic and exogenously induced lung injury/remodeling.

Evaluation of intra- and interatrial synchronization in patients with paroxysmal atrial fibrillation by dual gate Doppler

Objective To evaluate intra- and interatrial synchronization in patients with paroxysmal atrial fibrillation (PAF) by dual gate Doppler and discuss the predictive value of atrial asynchrony for detecting PAF. Methods Twenty-nine patients with PAF as AF group and 24 healthy volunteers as control group underwent echocardiography. The time interval of the onset of a′ wave between mitral annular septal and lateral site was T1 by dual gate Doppler, which was used to evaluate left atrial synchronization. The time intervals from the onset of a′ wave at tricuspid annular right ventricular free wall site to a′ wave at tricuspid annular septal site and mitral annular lateral site were T2 and T3, which were respectively used to evaluate right atrial and interatrial synchronization. The greater time interval predicted the worse synchronization. Compared these indexes between two groups, the most valuable index was obtained and combined with left atrial volume index (LAVI) to predict PAF, its optimal values were found out by ROC curve. Results ①There were no significant differences in many other basic indexes between two groups (P>0.05). However, compared with control group, the ratio of early diastolic transmitral flow velocity (E) and mitral annular velocity of septal site (e′), the diameters and volume indexes of atria were significantly increased in AF group. ②T1, T2 and T3 (standardized before and after) increased significantly in AF group (P<0.01). Standardized T1 had the largest area under curve (AUC) for detecting PAF. The AUC of standardized T1 and LAVI were 76.6% and 84.1%. Standardized T1≥29.55 ms and LAVI≥21.60 ml/m2 were combined for detecting PAF (sensitivity 82.8%, specificity 79.2%, AUC 87.1%). ③Standardized T1 was positively correlated with age, left atrial systolic diameter, LAVI, RAVI and E/e′ (P<0.05). Conclusions Patients with PAF have worse intra- and interatrial synchronization and left atrial asynchrony can provide predictive value for detecting PAF. Dual gate Doppler is expected to be a new technique for evaluating intra- and interatrial synchronization accurately and detecting the risk of AF. Key words: Echocardiography; Atrial fibrillation; Atrial function; Dual Gate Doppler

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization.

Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA1-deficient knock-out (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA1 KO mice. Taken together, our data suggest that LPA-LPA1 signaling is critically required for septation during alveolarization.

Nasal Septal Deviation and Facial Skeletal Asymmetries.

During ontogeny, the nasal septum exerts a morphogenetic influence on the surrounding facial skeleton. While the influence of the septum is well established in long snouted animal models, its role in human facial growth is less clear. If the septum is a facial growth center in humans, we would predict that deviated septal growth would be associated with facial skeletal asymmetries. Using computed tomographic (CT) scans of n = 55 adult subjects, the purpose of this study was to test whether there is a correlation between septal deviation and facial asymmetries using three-dimensional (3D) geometric morphometric techniques. We calculated deviation as a percentage of septal volume relative to the volume of a modeled non-deviated septum. We then recorded skeletal landmarks representing the nasal, palatal, and lateral facial regions. Landmark data were superimposed using Procrustes analysis. First, we examined the correlation between nasal septal deviation and the overall magnitude of asymmetry. Next, we assessed whether there was a relationship between nasal septal deviation and more localized aspects of asymmetry using multivariate regression analysis. Our results indicate that while there was no correlation between septal deviation and the overall magnitude of asymmetry, septal deviation was associated with asymmetry primarily in the nasal floor and the palatal region. Septal deviation was unassociated with asymmetries in the lateral facial skeleton. Though we did not test the causal relationship between nasal septal deviation and facial asymmetry, our results suggest that the nasal septum may have an influence on patterns of adult facial form.

Histological Structure and Vascularity of Hysteroscopically Removed Uterine Septa in Patients With Primary Infertility and Patients With Recurrent Pregnancy Loss

ObjectiveTo examine the histological structure and vascularity of uterine septa in patients with unexplained primary infertility and patients with recurrent pregnancy loss (RPL). DesignCase-control study (Canadian Task Force classification II-2). SettingKasr Al Aini Hospital, Cairo University, Egypt. Patients and InterventionsA total of 41 patients with uterine septa presenting with either unexplained primary infertility or RPL underwent 3-dimensional (3D) and power Doppler (PD) ultrasound to calculate the septum volume, septal vascularization index (VI), and myometrial VI. Hysteroscopically removed septa were examined histologically for myometrial and fibrous tissue content. Measurements and Main ResultsSeptal characteristics differed between the primary infertility group (24 patients) and the RPL group (17 patients). Mean septal VI was significantly higher in the RPL group compared with the infertility group (18.39% ± 7.57% vs 11.67% ± 4.56%; p = .003), as was meptal myometrial area (20.74% ± 5.97% vs 13.57% ± 5.55%; p < .001). In both groups, septal VI was strongly correlated with myometrial VI and myometrial content, but not with fibrous tissue content. ConclusionUterine septa of patients with RPL are more vascularized and contain more muscular tissue compared with those of patients with primary unexplained infertility.