Ultrasound evaluation of portal venous gas and its mimics.

Portal venous gas on abdominal ultrasound classically represents an indirect indicator of bowel ischemia, a critical condition which poses a high patient mortality and therefore warrants emergent corrective action. While the classic appearance of portal venous gas on ultrasound is well-described in the literature, the characteristic descriptors are nonspecific and may actually represent other less emergent mimics. Therefore, while radiologists should remain vigilant for the detection of findings corresponding to portal venous gas, they should also be aware of similar-appearing entities in order to provide the most accurate diagnosis. This pictorial essay will open with imaging examples of true portal venous gas attributable to bowel ischemia and describe the classic features which should alert radiologists to this specific diagnosis. Subsequently, this pictorial essay will provide imaging examples of other various other clinical entities which on ultrasound may share similar imaging characteristics. An important objective of this pictorial essay is to highlight distinguishing imaging features along with specific clinical circumstances for each pathological entity which can direct radiologists into identifying the correct diagnosis.

Factors associated with reporting left ventricular ejection fraction with 3D echocardiography in real-world practice.

BACKGROUND: Guidelines recommend 3D echocardiography (3DE) to assess left ventricular ejection fraction (LVEF) on transthoracic echocardiogram (TTE) when possible, but it is unclear which factors are most strongly associated with reporting 3DE LVEF in real-world practice. METHODS: We evaluated 3DE LVEF reporting by age, sex, BMI, TTE location and variation in reporting by sonographer and reader. All TTEs were performed without contrast enhancement agent at a large medical center from 9/2015 to 12/2020 using ultrasound machines capable of 3DE. We used multivariable logistic regression to assess which factors were most associated with reporting 3DE LVEF. RESULTS: Among 35 641 TTEs included in this study, 57.4% were performed on women. 3DE LVEF was reported on 18 391 TTEs (51.6% of cohort; 50.5% for women and 52.4% for men). Portable inpatient TTEs (n = 5569) had the lowest rates of 3DE LVEF reporting (30.9%), while general outpatient TTEs (n = 15 933) had greater reporting (56.9%). Outpatient TTEs with an indication for chemotherapy (n = 3244) had the highest rates of 3DE LVEF (87.2%). The median (IQR) percentage of TTEs reporting 3D LVEF was 52.7% (43.1%-68.1%) among sonographers and 51.6% (46.5%-59.6%) among readers. Among 20082 (56.3%) TTEs with 3DE LVEF measured by sonographers, 91.6% were included by readers in the final report. After adjustment, performing sonographer in the highest reporting quartile was most strongly associated with reporting 3DE LVEF (OR 7.04, 95% CI 6.55-7.56), while an inpatient portable study had the strongest negative association for reporting (OR .38, 95% CI .35-.40). CONCLUSIONS: Use of 3DE LVEF in real-world practice varies substantially based on performing sonographer and is low for hospitalized patients, but can be frequently used for chemotherapy. Initiatives are needed to increase sonographer 3DE acquisition in most clinical settings.

Tricuspid and mitral remodelling in atrial fibrillation: a three-dimensional echocardiographic study.

AIMS: Atrial fibrillation (AF) is associated with atrial enlargement, mitral annulus (MA) and tricuspid annulus (TA) dilation, and atrial functional regurgitation (AFR). However, less is known about the impact of AF on both atrioventricular valves in those with normal and abnormal ventricular function. We aimed to compare the remodelling of the TA and MA in patients with non-valvular AF without significant AFR. METHODS AND RESULTS: Ninety-two patients referred for transoesophageal echocardiography were included and categorized into three groups: (i) AF with normal left ventricular (LV) function (Normal LV-AF), n = 36; (ii) AF with LV systolic dysfunction (LVSD-AF), n = 29; and (iii) Controls in sinus rhythm, n = 27. Three-dimensional MA and TA geometry were analysed using automated software. In patients with AF regardless of LV function, the MA and TA areas were larger compared with controls (LVSD-AF vs. Normal LV-AF vs. Controls, end-systolic MA: 5.2 ± 1.1 vs. 4.5 ± 0.7 vs. 3.9 ± 0.7 cm2/m2; end-systolic TA: 5.6 ± 1.3 vs. 5.3 ± 1.3 vs. 4.1 ± 0.7 cm2/m2; P < 0.05 for each comparison with Controls). TA and MA areas were not statistically different between the two AF groups. The TA increase over controls was greater than that of the MA in the Normal LV-AF group (27.7% vs. 15.6%, P = 0.041). Conversely, in the LVSD-AF group, MA and TA increased similarly (35.9% vs. 32.4%, P = 0.660). CONCLUSION: Patients with AF showed dilation of both TA and MA compared with patients in sinus rhythm. In patients with normal LV function, AF was associated with greater TA dilation than MA dilation whereas in patients with LVSD the TA and MA were equally dilated.

Changes in left atrial appendage orifice following percutaneous left atrial appendage closure using three-dimensional echocardiography.

Percutaneous left atrial appendage (LAA) occlusion is increasingly performed in patients with atrial fibrillation and long-term contraindications for anticoagulation. Our aim was to evaluate the effects of LAA occlusion with the Watchman device on the geometry of the LAA orifice and assess its impact on the adjacent left upper pulmonary vein (LUPV) hemodynamics. We included 50 patients who underwent percutaneous LAA occlusion with the Watchman device and had acceptable three-dimensional transesophageal echocardiography images of LAA pre- and post-device placement. We measured offline the LAA orifice diameters in the long axis, and the minimum and maximum diameters, circumference, and area in the short axis view. Eccentricity index was calculated as maximum/minimum diameter ratio. The LUPV peak S and D velocities pre- and post-procedure were also measured. Patients were elderly (mean age 76 ± 8 years), 30 (60%) were men. There was a significant increase of all LAA orifice dimensions following LAA occlusion: diameter 1 (pre-device 18.1 ± 3.2 vs. post-device 21.5 ± 3.4 mm, p < 0.001), diameter 2 (20.6 ± 3.9 vs. 22.1 ± 3.6 mm, p < 0.001), minimum diameter (17.6 ± 3.1 vs. 21.3 ± 3.4 mm, p < 0.001), maximum diameter (21.5 ± 3.9 vs. 22.4 ± 3.6 mm, p = 0.022), circumference (63.6 ± 10.7 vs. 69.6 ± 10.5 mm, p < 0.001), and area (3.1 ± 1.1 vs. 3.9 ± 1.2 cm2, p < 0.001). Eccentricity index decreased after procedure (1.23 ± 0.16 vs. 1.06 ± 0.06, p < 0.001). LUPV peak S and D velocities did not show a significant difference (0.29 ± 0.15 vs. 0.30 ± 0.14 cm/s, p = 0.637; and 0.47 ± 0.19 vs. 0.48 ± 0.20 cm/s, p = 0.549; respectively). LAA orifice stretches significantly and it becomes more circular following LAA occlusion without causing a significant impact on the LUPV hemodynamics.

Understanding tricuspid valve remodelling in atrial fibrillation using three-dimensional echocardiography.

AIMS: Atrial fibrillation (AF) has been associated with tricuspid annulus (TA) dilation in patients with severe functional tricuspid regurgitation (TR); however, the impact of AF is less clear in patients without severe TR. Our aim was to characterize TA remodelling in patients with AF in the absence of severe TR using 3D transoesophageal echocardiography (TOE). METHODS AND RESULTS: Ninety patients underwent clinically indicated transthoracic and TOE: non-structural (NS)-AF (n = 30); AF with left heart disease (LHD) (n = 30), and controls in sinus rhythm (n = 30). Three-dimensional TOE datasets were analysed to measure TA dimensions using novel dedicated tricuspid valve software. The NS-AF group showed biatrial dilatation and normal right ventricular (RV) size with decreased longitudinal function compared to controls, whereas the LHD-AF group showed biatrial dilatation, RV enlargement, decreased biventricular function, and higher systolic pulmonary artery pressure compared with the other groups. Indexed TA area, minimum diameter, maximum diameter, and total perimeter were significantly larger in the NS-AF group than in controls (measurements in end-diastole: 6.4 ± 1.1 vs. 5.0 ± 0.6 cm2/m2, 1.8 ± 0.3 vs. 1.6 ± 0.2 cm/m2, 2.1 ± 0.3 vs. 1.9 ± 0.2 cm/m2, and 6.6 ± 0.9 vs. 5.9 ± 0.7 cm/m2, respectively, all P < 0.05). There was no significant difference in any indexed TA parameter between AF groups. TA circularity index (ratio between minimum and maximal diameters) and TA fractional area change between end-diastole and end-systole were no different among the three groups. CONCLUSION: AF is associated with right atrial and tricuspid annular remodelling independent of the presence of LHD in patients with intrinsically normal tricuspid leaflets without severe TR.

The feasibility of contrast echocardiography in the assessment of right ventricular size and function.

BACKGROUND: Right ventricle (RV) evaluation requires dedicated imaging to achieve a comprehensive functional and anatomical assessment. Right ventricular imaging could be technically difficult which results in suboptimal visibility and inconsistent assessment between observers. The aim of this study was to assess feasibility and the additive value of contrast enhancement for right ventricular evaluation. METHODS: Eighty patients referred for clinically indicated echocardiography studies were included. Patients with irregular rhythms were excluded. Dedicated RV-focused view was attained; RV dimensions measured, and RV segment visualization and wall motion were assessed with and without contrast enhancement. Paired sample t test was used to compare continuous variables, Wilcoxon signed-rank test to compare segments visualization on enhanced versus (vs) nonenhanced images, and Cohen kappa coefficient to assess the agreement of wall motion between two observers. Reproducibility was measured by the absolute mean difference method. RESULTS: A total of 240 total segments of 80 patients were analyzed, and 178 (74%) were visible on unenhanced while 221 (92%) on enhanced images, P < .05. Further, RV measurements on enhanced images were consistently larger on RV focused, SAX, and RVOT. Inter- and intra-observer reproducibility showed a higher reproducibility with a lower bias on enhanced images. Absolute agreement on RV segmental wall motion between two independent observers was higher on enhanced images. Percent agreement was 78% on UE vs 89% on CE. CONCLUSION: Contrast RV imaging is feasible and improves RV segment visualization and inter-observer agreement. Compared with unenhanced images, RV measurements on contrast images are larger and more reproducible with lower bias.

Rocaglates as dual-targeting agents for experimental cerebral malaria.

Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.

Lower Wingate Test Power Outcomes From "All-Out" Pretest Pedaling Cadence Compared With Moderate Cadence.

The aim of the present study was to determine the effect of different pretest pedaling cadences on power outcomes obtained during the Wingate Anaerobic Test (WAnT). Vigorously exercising adult men (n = 14, 24.9 ± 1.2 years) and women (n = 14, 20.4 ± 0.6 years) participated in a randomized crossover study during which they performed the 30-second WAnT on a mechanically braked cycle ergometer (0.075 kg·kg(-1) body weight) under 2 conditions. Participants pedaled maximally with an unloaded flywheel during 5 seconds before resistance was applied and the test began (FAST). In another trial, participants maintained a moderate cadence (80 revolutions per minute [rpm]) during 5 seconds before the test began (MOD). All other components of the WAnT were identical. Peak power (PP), mean power (MP), minimum power (MinP), fatigue index (%FAT), and maximum cadence during test were recorded. Comparisons were made using a 2 × 2 factorial repeated-measures analysis of variance. Regardless of gender, the FAST condition resulted in 22.2% lower PP (612.6 ± 33.0 W vs. 788.3 ± 43.5 W), 13.3% lower MP (448.4 ± 22.2 W vs. 517.2 ± 26.4 W), 11.7% lower MinP (280.9 ± 14.8 W vs. 318.3 ± 17.2 W), and 9.0% lower %FAT (53.5 ± 1.3% vs. 58.8 ± 1.5%) than MOD condition (p < 0.01; mean ± SD). Similar outcomes were observed within gender. The authors conclude that practitioners of the WAnT should instruct participants to maintain a moderate pedal cadence (∼80 rpm) during 5 seconds before the test commences to avoid bias from software sampling and peripheral fatigue. Standardizing the pretest pedal cadence will be important to exercise testing professionals who compare data with norms or generate norms for specific populations.

A purine analog synergizes with chloroquine (CQ) by targeting Plasmodium falciparum Hsp90 (PfHsp90).

BACKGROUND: Drug resistance, absence of an effective vaccine, and inadequate public health measures are major impediments to controlling Plasmodium falciparum malaria worldwide. The development of antimalarials to which resistance is less likely is paramount. To this end, we have exploited the chaperone function of P. falciparum Hsp90 (PfHsp90) that serves to facilitate the expression of resistance determinants. METHODS: The affinity and activity of a purine analogue Hsp90 inhibitor (PU-H71) on PfHsp90 was determined using surface plasmon resonance (SPR) studies and an ATPase activity assay, respectively. In vitro, antimalarial activity was quantified using flow cytometry. Interactors of PfHsp90 were determined by LC-MS/MS. In vivo studies were conducted using the Plasmodium berghei infection mouse model. RESULTS: PU-H71 exhibited antimalarial activity in the nanomolar range, displayed synergistic activity with chloroquine in vitro. Affinity studies reveal that the PfHsp90 interacts either directly or indirectly with the P. falciparum chloroquine resistance transporter (PfCRT) responsible for chloroquine resistance. PU-H71 synergized with chloroquine in the P.berghei mouse model of malaria to reduce parasitemia and improve survival. CONCLUSIONS: We propose that the interaction of PfHsp90 with PfCRT may account for the observed antimalarial synergy and that PU-H71 is an effective adjunct for combination therapy.

Synthesis and anti-Plasmodium activity of benzimidazole analogues structurally related to astemizole.

A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.

The interaction of imidazole-, imidazolium-, and tetrazolium-containing compounds with DNA.

The interaction between DNA and members of series of bivalent imidazole compounds, monovalent and bivalent imidazolium compounds, and monovalent and bivalent tetrazolium compounds, which had been synthesized and evaluated for their anti-Plasmodium activity, has been examined using the displacement of SYBR Green I as a measure of competitive binding. The degree of interaction with DNA appears to be dependent on both hydrophobic and charge-pairing interactions.

Antimalarial activities of 6-iodouridine and its prodrugs and potential for combination therapy.

Resistance by Plasmodium falciparum to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (15), a novel and potent inhibitor of orotidine 5'-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by P. chabaudi chabaudi. Compound 15 exhibited promising antimalarial activity against P. falciparum, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with 15. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with 15. In drug combination studies, compound 15 showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of 15 exhibited superior antimalarial efficacy. Antimalarial activities of 15 and its prodrugs and potential for combination therapy are discussed in the context of novel strategies.

Novel cytidine-based orotidine-5'-monophosphate decarboxylase inhibitors with an unusual twist.

Orotidine-5'-monophosphate decarboxylase (ODCase) is an interesting enzyme with an unusual catalytic activity and a potential drug target in Plasmodium falciparum, which causes malaria. ODCase has been shown to exhibit unusual and interesting interactions with a variety of nucleotide ligands. Cytidine-5'-monophosphate (CMP) is a poor ligand of ODCase, and CMP binds to the active site of ODCase with an unusual orientation and conformation. We designed N3- and N4-modified CMP derivatives as novel ligands to ODCase. These novel CMP derivatives and their corresponding nucleosides were evaluated against Plasmodium falciparum ODCase and parasitic cultures, respectively. These derivatives exhibited improved inhibition of the enzyme catalytic activity, displayed interesting binding conformations and unusual molecular rearrangements of the ligands. These findings with the modified CMP nucleotides underscored the potential of transformation of poor ligands to ODCase into novel inhibitors of this drug target.

Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquine and artemisinin.

Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [K(d)] of 40 µM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (K(d) of 224 µM) more tightly than PfHsp90 (K(d) of 7,010 µM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.

Identifying mechanisms by which Escherichia coli O157:H7 subverts interferon-γ mediated signal transducer and activator of transcription-1 activation.

Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon-gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein.

The anti-malarial activity of bivalent imidazolium salts.

A series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized and evaluated for their ability to inhibit the replication of Plasmodium falciparum cultures. The activity and selectivity of the compounds for P. falciparum cultures were found to depend on the presence of electron-deficient rings that were spaced an appropriate distance apart. The activity of the compounds was not critically dependent on the nature of the linker between the electron-deficient rings, an observation that suggests that the rings were responsible for the primary interaction with the molecular target of the compounds in the parasite. The bivalent imidazolium and triazolium compounds disrupted the process whereby merozoites gain entry into erythrocytes, however, they did not appear to prevent merozoites from forming. The compounds were also found to be active in a murine Plasmodium berghei infection, a result consistent with the compounds specifically interacting with a parasite component that is required for replication and is conserved between two Plasmodium species.

Novel interactions of fluorinated nucleotide derivatives targeting orotidine 5'-monophosphate decarboxylase.

Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 ± 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations.

Stenotrophomonas maltophilia in cystic fibrosis: serologic response and effect on lung disease.

RATIONALE: Stenotrophomonas maltophilia is one of the more common multidrug-resistant organisms isolated from the respiratory tract of patients with cystic fibrosis (CF), but the effect of chronic S. maltophilia infection on CF lung disease is unknown. OBJECTIVES: To determine the impact of chronic S. maltophilia infection on lung disease in CF. METHODS: We developed a serologic assay specific for S. maltophilia and in a cross-sectional study, measured serum antibodies to S. maltophilia in patients with CF to determine if a definition of chronic S. maltophilia isolation based on culture results corresponded to an immunologic response (serologic study). We then used this validated definition to examine the effect of chronic S. maltophilia on the severity of lung disease in a retrospective cohort study using the Toronto CF Database from 1997-2008 (cohort study). MEASUREMENTS AND MAIN RESULTS: Serum antibody levels to S. maltophilia were measured in 179 patients with CF. Patients with chronic S. maltophilia had significantly higher mean antibody levels to S. maltophilia flagellin (P < 0.0001) and whole cell (P = 0.0004) compared with patients with intermittent or no S. maltophilia. The cohort study included 692 patients with an average follow-up of 8.3 years. In an adjusted log linear model, patients with chronic S. maltophilia infection had a significantly increased risk of pulmonary exacerbation requiring hospitalization and antibiotics compared with patients who had never had S. maltophilia (relative risk = 1.63; P = 0.0002). CONCLUSIONS: Chronic S. maltophilia infection in patients with CF is associated with a specific immune response to this organism and is an independent risk factor for pulmonary exacerbations.