Echocardiography-derived septal curvature correlated with invasive hemodynamics in pediatric pulmonary hypertension.

BACKGROUND: Right ventricular function and afterload are associated with clinical outcomes in pulmonary hypertension (PH). MRI-derived interventricular septal curvature has been associated with invasive hemodynamics in PH patients. This study sought to determine the relationship of echocardiography derived septal curvature with invasive hemodynamics in pediatric PH patients. METHODS: A single center chart review identified 56 pediatric patients with PH and 50 control patients with adequate echocardiography to assess septal curvature within one month of initial cardiac catheterization. Echocardiographic indices of septal flattening including end-systolic eccentricity index (EIs), maximum EI (EImax), minimum septal curvature (SCmin), and average SC (SCavg) were determined. RESULTS: PH patients had a median right ventricular systolic pressure of 64 mmHg (interquartile range (IQR) 48-81), mean pulmonary artery pressure of 44 mmHg (IQR 32-57), pulmonary vascular resistance of 7.9 iWU (IQR 4.8-12.9), and pulmonary capillary wedge pressure of 10 mmHg (IQR 8-12). Patients with PH had higher EIs and EImax and lower SCmin and SCavg compared to control patients. SCavg demonstrated the strongest association with right ventricular systolic pressure (R2 0.73, p < 0.0001), mean pulmonary artery pressure (R2 0.63, p < 0.0001), and pulmonary vascular resistance (R2 0.47, p < 0.0001). All septal curvature indices were associated with the composite adverse outcome, including Potts shunt, lung transplantation, and death. SCmin (HR 0.29; 95%CI 0.07-0.97) and SCavg (HR 0.15; 95%CI 0.03-0.72) were the only septal flattening indices associated with death. CONCLUSIONS: Echocardiography derived septal curvature is a non-invasive marker of ventricular afterload and adverse outcomes.

Direct health care costs of managing perianal Crohn's Disease in a population based cohort.

BACKGROUND: Crohn's disease is a chronic condition that places a high health care cost burden. Perianal Crohn's disease (pCD) is a difficult phenotype to treat due to poorer response to medical and surgical therapies. No study has assessed if this translates to higher healthcare costs. The aim is to assess the cost of treating pCD and compare to the cost of non-perianal Crohn's disease (CD). METHODS: This is a retrospective case-control cohort study in a population-based setting. The direct healthcare costs for patients with pCD were calculated over 12 months. Data was compared to the control group of non-perianal CD patients on biologic treatment, with the use of the Mann-Whitney rank test to assess significance. RESULTS: 187 Crohn's patients were included (39 pCD, 148 CD). Per patient, annual cost was €17,779.19 and €17,576.86 respectively (p = .9391). Medications were responsible for the majority of cost at 78% and 92% of total cost in pCD and CD, respectively (€13,886.04 in pCD, and €16,007.10 in CD), of which biologics were the main driver. Surgical costs were higher in the pCD group due to a higher cost of luminal surgery (€2633.88 in pCD vs €209.79 in CD, p = .0270). CONCLUSION: This is the first study to assess the cost of treating perianal Crohn's disease in a real-world population. Although the costs were similar overall to non-perianal Crohn's patients, the perianal cohort had higher surgical costs from luminal surgery. This demonstrates the potential to apply early intensive treatment to reduce future surgical cost.

Crohn's disease is a lifelong disease where high-cost drugs are required to achieve optimal outcomes. There is minimal data regarding the cost of managing perianal fistulising Crohn's disease and whether the clinical complexity of these patients translates to higher healthcare costs. Costs were similar between luminal Crohn's disease patients treated with a biologic and those with perianal disease, though the distribution of costs varied. Knowing this distribution will allow for more effective allocation of resources.

The Fontan Pathway: Change in Dimension and Catheter-Based Intervention over Time.

An unobstructed Fontan pathway is essential for optimal hemodynamics. We hypothesize that more extracardiac conduit (ECC) Fontan pathways develop obstruction compared to lateral tunnel (LT) Fontans and that the dilation typically observed in LTs results in similar mid-term clinical outcomes. A single-center, retrospective study was done including all Fontan cardiac catheterizations from 2006 to 2019. Angiography and medical records were reviewed to define Fontan pathway dimensions, interventions, and clinical outcomes. 232 patients underwent cardiac catheterization, where 60% were ECCs and 30% LTs. The minimum cross-sectional area (CSA) of ECCs was significantly smaller than LTs and LTs dilated over time. 13% of patients had Fontan pathway stenting at a median age of 16.2 years. The minimum CSA for patients who underwent intervention was significantly smaller than patients who did not. Lower weight at Fontan surgery was associated with intervention on the Fontan pathway, with a threshold weight of 15 kg for patients with an ECC. The median follow-up was 3.3 years. Patients who had Fontan pathway intervention were not more likely to experience the composite adverse clinical outcome. LTs were more likely than ECCs to have worse clinical outcome, when liver fibrosis was included. This is the first study to describe angiographic dimensions of the Fontan pathway in a large number of patients over time. ECCs tend to become stenotic. Lower weight at Fontan surgery is a potential risk for Fontan pathway intervention. LTs may experience worse clinical outcomes in follow-up. This information can help inform the optimal timing and method of post-Fontan surveillance.

Molecular Identification of Mutations Conferring Resistance to Azoxystrobin in Cercospora nicotianae.

Cercospora nicotianae, the causal agent of frogeye leaf spot (FLS) of tobacco, has been exposed to quinone outside inhibitor (QoI) fungicides for more than a decade through azoxystrobin applications targeting other major foliar diseases. From 2016 to 2018, a total of 124 isolates were collected from tobacco fields throughout Kentucky. Sensitivity of these isolates to azoxystrobin was previously characterized by determining the effective concentration to inhibit 50% conidial germination (EC50). Based on azoxystrobin EC50, isolates were categorized into three discrete groups: high sensitivity (<0.08 µg/ml), moderate sensitivity (0.14 to 0.64 µg/ml), and low sensitivity (>1.18 µg/ml). Variability in sensitivity in a limited number of C. nicotianae isolates was previously shown to be a result of resistance mutations in the fungicide target gene. To improve understanding of C. nicotianae cytochrome b (cytb) structure, the gene was cloned from three isolates representing each EC50 group, and sequences were compared. Our analysis showed that cytb gene in C. nicotianae consists of 1,161 nucleotides encoding 386 amino acids. The cytb sequence among the cloned isolates was identical with the exception of the F129L and G143A point mutations. To more rapidly determine the resistance status of C. nicotianae isolates to azoxystrobin, a polymerase chain reaction (PCR) assay was developed to screen for mutations. According to this assay, 80% (n = 99) of tested C. nicotianae isolates carried an F129L mutation and were moderately resistant to azoxystrobin, and 7% (n = 9) carried the G143A mutation and were highly resistant. A receiver operating characteristic curve analysis suggested the PCR assay was a robust diagnostic tool to identify C. nicotianae isolates with different sensitivity to azoxystrobin in Kentucky tobacco production. The prevalence of both the F129L and G143A mutations in C. nicotianae from Kentucky differs from that of other pathosystems where resistance to QoI fungicides has been identified, in which the majority of sampled isolates of the pathogen species have a broadly occurring cytb mutation.

Cytochrome b Mutations F129L and G143A Confer Resistance to Azoxystrobin in Cercospora nicotianae, the Frogeye Leaf Spot Pathogen of Tobacco.

Azoxystrobin is the only synthetic, systemic fungicide labeled in the United States for management of frogeye leaf spot (FLS) of tobacco (Nicotiana tabacum L.), caused by Cercospora nicotianae. Though traditionally considered a minor disease in the United States, FLS has recently become yield and quality limiting. In 2016 and 2017, 100 C. nicotianae isolates were collected from symptomatic tobacco from eight counties in Kentucky, United States. Prior to azoxystrobin sensitivity testing, some C. nicotianae isolates were found to utilize the alternative oxidase pathway and, after assay comparisons, conidial germination was utilized to evaluate sensitivity in C. nicotianae as opposed to mycelial growth. Azoxystrobin sensitivity was determined by establishing the effective concentration to inhibit 50% conidial germination (EC50) for 47 (in 2016) and 53 (in 2017) C. nicotianae isolates. Distributions of C. nicotianae EC50 values indicated three qualitative levels of sensitivity to azoxystrobin. Partial cytochrome b sequence, encompassing the F129L and G143A mutation sites, indicated single-nucleotide polymorphisms (SNPs) conferring the F129L mutation in C. nicotianae of moderate resistance (azoxystrobin at 0.177 ≤ EC50 ≤ 0.535 µg/ml) and the G143A mutation in isolates with an azoxystrobin-resistant phenotype (azoxystrobin EC50 > 1.15 µg/ml). Higher frequencies of resistant isolates were identified from greenhouse transplant (4 of 17) and conventionally produced (58 of 62) tobacco samples, as compared with field-grown tobacco (<4 weeks prior to harvest; 4 of 62) or organically produced samples (1 of 7), respectively. Together, these results suggest that resistance to azoxystrobin in C. nicotianae occurs broadly in Kentucky, and generate new hypotheses about selection pressure affecting resistance mutation frequencies.

Enhanced Quadrupole and Octupole Strength in Doubly Magic

The first 2^{+} and 3^{-} states of the doubly magic nucleus ^{132}Sn are populated via safe Coulomb excitation employing the recently commissioned HIE-ISOLDE accelerator at CERN in conjunction with the highly efficient MINIBALL array. The ^{132}Sn ions are accelerated to an energy of 5.49 MeV/nucleon and impinged on a ^{206}Pb target. Deexciting γ rays from the low-lying excited states of the target and the projectile are recorded in coincidence with scattered particles. The reduced transition strengths are determined for the transitions 0_{g.s.}^{+}→2_{1}^{+}, 0_{g.s.}^{+}→3_{1}^{-}, and 2_{1}^{+}→3_{1}^{-} in ^{132}Sn. The results on these states provide crucial information on cross-shell configurations which are determined within large-scale shell-model and Monte Carlo shell-model calculations as well as from random-phase approximation and relativistic random-phase approximation. The locally enhanced B(E2;0_{g.s.}^{+}→2_{1}^{+}) strength is consistent with the microscopic description of the structure of the respective states within all theoretical approaches. The presented results of experiment and theory can be considered to be the first direct verification of the sphericity and double magicity of ^{132}Sn.

The injured heart: early cardiac effects of hematopoietic stem cell transplantation in children and young adults.

We hypothesized that subclinical cardiac injury in the peri-transplant period is more frequent than currently appreciated in children and young adults. We performed echocardiographic screening on 227 consecutive patients prior to hematopoietic stem cell transplantation (HSCT), and 7, 30 and 100 days after transplant. We measured cardiac biomarkers cardiac troponin-I (cTn-I), and soluble suppressor of tumorigenicity 2 (sST2) prior to transplant, during conditioning, and days +7, +14, +28 and +49 in 26 patients. We subsequently analyzed levels of cTn-I every 48-72 h in 15 consecutive children during conditioning. Thirty-two percent (73/227) of patients had a new abnormality on echocardiogram. New left ventricular systolic dysfunction (LVSD) occurred in 6.2% of subjects and new pericardial effusion in 27.3%. Eight of 227 (3.5%) patients underwent pericardial drain placement, and 5 (2.2%) received medical therapy for clinically occult LVSD. cTn-I was elevated in 53.0% of all samples and sST2 in 38.2%. At least one sample had a detectable cTn-I in 84.6% of patients and an elevated sST2 in 76.9%. Thirteen of fifteen patients monitored frequently during condition had elevation of cTn-I. Echocardiographic and biochemical abnormalities are frequent in the peri-HSCT period. Echocardiogram does not detect all subclinical cardiac injuries that may become clinically relevant over longer periods.

Latrophilin receptors: novel bronchodilator targets in asthma.

BACKGROUND: Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. OBJECTIVES: To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. METHODS: Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. RESULTS: We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. CONCLUSIONS: Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.

Fragmented patterns of flood change across the United States.

Trends in the peak magnitude, frequency, duration, and volume of frequent floods (floods occurring at an average of two events per year relative to a base period) across the United States show large changes; however, few trends are found to be statistically significant. The multidimensional behavior of flood change across the United States can be described by four distinct groups, with streamgages experiencing (1) minimal change, (2) increasing frequency, (3) decreasing frequency, or (4) increases in all flood properties. Yet group membership shows only weak geographic cohesion. Lack of geographic cohesion is further demonstrated by weak correlations between the temporal patterns of flood change and large-scale climate indices. These findings reveal a complex, fragmented pattern of flood change that, therefore, clouds the ability to make meaningful generalizations about flood change across the United States.

Is calcaneal broadband ultrasound attenuation a valid index of dual-energy x-ray absorptiometry-derived bone mass in children?

OBJECTIVES: The aim of the current study was to assess whether calcaneal broadband ultrasound attenuation (BUA) can predict whole body and regional dual-energy x-ray absorptiometry (DXA)-derived bone mass in healthy, Australian children and adolescents at different stages of maturity. METHODS: A total of 389 boys and girls across a wide age range (four to 18 years) volunteered to participate. The estimated age of peak height velocity (APHV) was used to classify children into pre-, peri-, and post-APHV groups. BUA was measured at the non-dominant heel with quantitative ultrasonometry (QUS) (Lunar Achilles Insight, GE), while bone mineral density (BMD) and bone mineral content (BMC) were examined at the femoral neck, lumbar spine and whole body (DXA, XR-800, Norland). Associations between BUA and DXA-derived measures were examined with Pearson correlations and linear regression. Participants were additionally ranked in quartiles for QUS and DXA measures in order to determine agreement in rankings. RESULTS: For the whole sample, BUA predicted 29% of the study population variance in whole body BMC and BMD, 23% to 24% of the study population variance in lumbar spine BMC and BMD, and 21% to 24% of the variance in femoral neck BMC and BMD (p < 0.001). BUA predictions were strongest for the most mature participants (pre-APHV R2 = 0.03 to 0.19; peri-APHV R2 = 0.05 to 0.17; post-APHV R2 = 0.18 to 0.28) and marginally stronger for girls (R2 = 0.25-0.32, p < 0.001) than for boys (R2 = 0.21-0.27, p < 0.001). Agreement in quartile rankings between QUS and DXA measures of bone mass was generally poor (27.3% to 38.2%). CONCLUSION: Calcaneal BUA has a weak to moderate relationship with DXA measurements of bone mass in children, and has a tendency to misclassify children on the basis of quartile rankings.Cite this article: B. K. Weeks, R. Hirsch, R. C. Nogueira, B. R. Beck. Is calcaneal broadband ultrasound attenuation a valid index of dual-energy x-ray absorptiometry-derived bone mass in children? Bone Joint Res 2016;5:538-543. DOI: 10.1302/2046-3758.511.BJR-2016-0116.R1.

Exploring the association between a cholecystokinin promoter polymorphism (rs1799923) and posttraumatic stress disorder in combat veterans.

BACKGROUND: Cholecystokinin (CCK) is a neuropeptide that has been implicated in understanding the acquisition and extinction of fear. Research on CCK in anxiety has primarily focused on understanding panic attacks and panic disorder. Emerging data suggests that CCK may also hold promise in understanding the development and maintenance of posttraumatic stress disorder (PTSD). METHOD: The present study examined whether a single nucleotide polymorphism in the promoter region of the CCK gene (C>T; rs1799923) was associated with an increased prevalence of PTSD as well as with severity of PTSD symptoms among a sample of 457 combat veterans. RESULTS: Results demonstrated that participants with either the heterozygous or homozygous T allele had an increased prevalence of PTSD relative to participants with the CC genotype (OR=2.17; 95% CI [1.37-3.43]). LIMITATIONS: The relatively small sample size precluded examination of racial/ethnic differences. Findings were also limited by the absence of a systematic assessment of comorbid anxiety psychopathology. CONCLUSIONS: These data offer preliminary evidence supporting an association between the rs1799923 polymorphism in the CCK gene and PTSD. Additional research is needed to better understand the nature of this relationship.

Azithromycin suppresses P. gingivalis LPS-induced pro-inflammatory cytokine and chemokine production by human gingival fibroblasts in vitro.

OBJECTIVE: Azithromycin is a macrolide antibiotic that appears to have both antibacterial and anti-inflammatory properties. This study aimed to investigate the effect of azithromycin on the production of pro-inflammatory cytokines and chemokines by human gingival fibroblasts (HGF) in vitro. MATERIALS AND METHODS: The effects of azithromycin (0.1 to 10 µg/mL) on the production of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), and growth-regulated oncogene (GRO) by human gingival fibroblasts cultured in the presence or absence of Porphyromonas gingivalis lipopolysaccharide (LPS) was studied. Cytokine and chemokine protein levels in the culture supernatant were assessed using a Luminex® multiplex immunoassay. RESULTS: P. gingivalis LPS induced cytokine/chemokine (IL-6, IL-8, MCP-1, and GRO) protein production in HGFs, and this effect was suppressed by azithromycin at all concentrations tested. CONCLUSIONS: This study demonstrates that azithromycin suppresses P. gingivalis LPS-induced cytokine/chemokine protein production in HGF, which may explain some of the clinical benefits observed with the adjunctive use of azithromycin in the treatment of periodontitis. CLINICAL RELEVANCE: The current study examines the anti-inflammatory properties of azithromycin which may make it useful as an adjunct treatment to periodontitis. Specifically, we used azithromycin to modulate the production of pro-inflammatory cytokines by gingival fibroblasts known to be important in periodontal inflammation.

Antibacterial and immunomodulatory properties of azithromycin treatment implications for periodontitis.

Macrolide antibiotics have been found to possess not only antimicrobial properties, but also modulate inflammation. In this review the multi-faceted properties of azithromycin are discussed. Due to the unique anti-inflammatory and antimicrobial properties, macrolides, and especially azithromycin, are currently used for a number of conditions which have both an inflammatory and microbial component. For the same reason, azithromycin may be of value as an adjunct in the management of periodontitis which, although driven by an infectious component, is largely a result of uncontrolled chronic inflammation.

Azithromycin in periodontal treatment: more than an antibiotic.

Azithromycin is a macrolide antibiotic used extensively in medicine for the treatment of a wide range of infections such as upper respiratory tract infections, middle ear infections, sexually transmitted infections and trachoma. It is also effective against the most common periodontopathogens. The versatility of the macrolides extends beyond their antibiotic properties as a result of their well-documented immune-modulating/anti-inflammatory effects. Macrolides, including azithromycin, are therefore used to treat diseases not associated with bacteria, such as severe asthma, chronic obstructive pulmonary diseases and, more recently, cystic fibrosis. Azithromycin is concentrated in neutrophils, macrophages and particularly fibroblasts; all of these cells are central players in the pathogenesis of most periodontal diseases. This paper reviews the diverse properties of azithromycin and the clinical periodontal studies of its effects in both the treatment of periodontitis and in resolving drug-related gingival overgrowth. Evidence exists to support the use of a single course of azithromycin in the treatment of advanced periodontal diseases. Azithromycin could have a triple role in the treatment and resolution of periodontal diseases: suppressing periodontopathogens, anti-inflammatory activity and healing through persistence at low levels in macrophages and fibroblasts in periodontal tissues, even after a single course of three tablets. If future periodontal research confirms these properties, it could become a valuable host-modulator in periodontal treatment.

Identifying genes in Fusarium verticillioides through forward and reverse genetics.

The increasing availability of sequenced genomes for plant pathogenic fungi has revolutionized molecular plant pathology in recent years. However, the genetic regulatory networks underlying many important components of pathogenesis remain poorly defined. Although the protocols outlined in this chapter can be utilized to identify genes regulating a wide range of biological processes in many filamentous fungi, we focus on describing how to identify genes through forward and reverse genetics, using the plant pathogenic fungus Fusarium verticillioides as a model for the protocol. Specifically, this chapter explains how to create a collection of insertional mutants via Restriction Enzyme Mediated Integration (REMI) and how to screen mutants with a high-throughput method to visualize defects in amylolysis. Next, techniques are described to define the genomic lesions in REMI mutants with genome-walker PCR in order to identify candidate genes. Finally, protocols are presented describing a reverse-genetic approach to disrupt candidate genes in the wild-type strain with a split-marker strategy to confirm the phenotype observed in the REMI mutant.

Periodontal healing and bone regeneration in response to azithromycin.

Azithromycin, first synthesized in 1980, is a macrolide antibiotic related to erythromycin. It is widely used by the medical profession as a broad-spectrum antibiotic in the treatment of pneumonia, urinary tract infections and tonsillitis. In addition to its antibiotic properties, azithromycin has immune-modulating effects and is used for this reason in the management of cystic fibrosis and chronic obstructive pulmonary diseases. The drug is taken up by neutrophils, macrophages and fibroblasts, and is slowly released by these cells. Three diverse case reports are presented in which a single course of azithromycin (consisting of one 500 mg tablet being taken a day for three days) was prescribed before any periodontal intervention occurred. Azithromycin was the principal mode of treatment of severe chronic and aggressive periodontitis in Cases 1 and 2. Azithromycin, together with monthly subgingival debridement, was the treatment in Case 3 (severe chronic periodontitis in a poorly controlled diabetic complicated by gingival overgrowth related to medication with a calcium channel blocker). Favourable resolution of inflammation, reduction in pocket depths and evidence of bone regeneration were evident, even when no periodontal treatment had occurred. In Case 3, resolution of gingival overgrowth occurred over eight months. The potential implications for periodontal management, understanding of the pathogenesis of periodontal diseases and periodontal research are briefly discussed.

[Humor therapy in the depressed elderly: results of an empirical study]. / Humortherapie bei alten Menschen mit einer Depression: Ergebnisse einer empirischen Untersuchung.

BACKGROUND: Positive effects of humor on older patients with depressive symptoms have been repeatedly reported. Empirical evidence, however, is rare. We investigated the effects of a standardized humor therapy group in a clinical context especially for older depressed patients. PATIENTS AND METHODS: For this purpose, an experimental group with treatment (52 patients participating in the humor group) was compared to a control group with no specific treatment (38 patients); all 90 participants had clinical depressive symptoms according to ICD-10 classification. Questionnaires (among them GDS, SF-12, State-Trait Cheerfulness Inventory, Satisfaction with Life Scale) were administered at two time points (pre- and post-treatment). RESULTS: From pre- to post-measurement, significant improvements could be shown only in the experimental group for resilience and satisfaction with life (p<0.05). Analyses of the subgroups with at least medium to severe depression showed further significant effects for cheerfulness, seriousness, bad mood, and satisfaction with life (p<0.05). These severely affected patients seemed to profit best from humor therapy. CONCLUSION: Our results indicate the efficacy of this specific therapeutic intervention for older depressed patients.