Synthesis and insecticidal activity of N-(5-phenylpyrazin-2-yl)-benzamide derivatives: Elucidation of mode of action on chitin biosynthesis through symptomology and genetic studies.

Among the six-membered heterocycles, the pyrazine ring is poorly explored in crop protection and does not feature in any product listed in the current IRAC MoA classification. In an effort to identify new leads for internal research, we synthesized a series of N-(5-phenylpyrazin-2-yl)-benzamide derivatives and evaluated them for their insecticidal activity. N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3 were prepared using an automated two-step synthesis protocol. These compounds were tested for their initial biological activity against a wide range of sucking and chewing insect pests and found to be active against lepidopterans only. More detailed experiments, including symptomology studies on the diamondback moth, Plutella xylostella (L.) and the Egyptian cotton leafworm, Spodoptera littoralis (Boisduval) showed that analog 3q causes severe abnormalities in the lepidopteran cuticle leading to larval mortality. Compound 3q shows strong potency against both P. xylostella and S. littoralis, whereas analog 3i shows better potency against S. littoralis causing also impaired cuticular structure and death of the larvae. Additionally, P. xylostella genetic studies showed that compound 3q resistance is linked to Chitin Synthase 1. Our studies show that N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3, and in particular analogs 3i and 3q, act as insect growth modulator insecticides. Conformational similarities with lufenuron are discussed.

Case report: Coronary allograft vasculopathy: an accurate reflection of the histopathological findings on cardiovascular magnetic resonance imaging.

Heart transplant recipients undergo extensive invasive and non-invasive postoperative screening to exclude complications, such as allograft rejection and vasculopathy. Cardiac magnetic resonance imaging is a non-invasive, non-irradiating, diagnostic tool for monitoring graft health and identifying possible tissue rejection or myocardial fibrosis. We describe the case of a 29-year-old female heart transplant recipient admitted to our care center with a worsening clinical condition. The patient underwent clinical evaluation, blood tests, including troponin I and N-terminal pro brain type natriuretic peptide, transthoracic echocardiography, invasive coronary angiography, and cardiovascular magnetic resonance imaging. Cardiovascular magnetic resonance imaging showed widespread sub-epicardial hyperintensity of the myocardial segments along the course of the coronary arteries. T2 mapping sequences showed an elevated value and the myocardial native T1 values and extracellular volume percentage were significantly increased. Late gadolinium enhancement demonstrated a diffuse sub-epicardial hypersignal along the lateral, free, and left ventricular walls. All the sequences evidenced widespread hyper-enhancement of epicardial fat along the course of the thickened main coronary artery walls. One month later, the recipient underwent re-transplantation due to progressive worsening of the clinical condition and refractoriness to intravenous medication. The anatomopathological findings of the explanted heart provided impressive visualization of structural and histopathological changes. These results could guide the tailoring of preventive therapeutic strategies and non-invasive monitoring of cardiac grafts.

Compressed Sensing Cardiac Cine Imaging Compared with Standard Balanced Steady-State Free Precession Cine Imaging in a Pediatric Population.

Purpose: To compare real-time compressed sensing (CS) and standard balanced steady-state free precession (bSSFP) cardiac cine imaging in children. Materials and Methods: Twenty children (mean age, 15 years ± 5 [SD], range, 7-21 years; 10 male participants) with biventricular congenital heart disease (n = 11) or cardiomyopathy (n = 9) were prospectively included. Examinations were performed with 1.5-T imagers by using both bSSFP and CS sequences in all participants. Quantification of ventricular volumes and function was performed for all images by two readers blinded to patient diagnosis and type of sequence. Values were correlated with phase-contrast flow measurements by one reader. Intra- and interreader agreement were analyzed. Results: There were no significant differences between ventricular parameters measured on CS compared with those of bSSFP (P > .05) for reader 1. Only ejection fraction showed a significant difference (P = .02) for reader 2. Intrareader agreement was considerable for both sequences (bSSFP: mean difference range, +1 to -2.6; maximum CI, +7.9, -13; bias range, 0.1%-4.1%; intraclass correlation coefficient [ICC] range, 0.931-0.997. CS: mean difference range, +7.4 to -5.6; maximum CI, +37.2, -48.8; bias range, 0.5%-7.5%; ICC range, 0.717-0.997). Interreader agreement was acceptable but less robust, especially for CS (bSSFP: mean difference range, +2.6 to -5.6; maximum CI, +60.7, -65.3; bias range, 1.6%-6.2%; ICC range, 0.726-0.951. CS: mean difference range, +10.7 to -9.1; maximum CI, +87.5, -84.6; bias range, 1.1%-17.3%; ICC range, 0.509-0.849). The mean acquisition time was shorter for CS (20 seconds; range, 17-25 seconds) compared with that for bSSFP (160 seconds; range, 130-190 seconds) (P < .001). Conclusion: CS cardiac cine imaging provided equivalent ventricular volume and function measurements with shorter acquisition times compared with those of bSSFP and may prove suitable for the pediatric population.Keywords: Compressed Sensing, Balanced Steady-State Free Precession, Cine Imaging, Cardiovascular MRI, Pediatrics, Cardiac, Heart, Cardiomyopathies, Congenital, Segmentation© RSNA, 2022.

Blood flow characteristics after aortic valve neocuspidization in paediatric patients: a comparison with the Ross procedure.

AIMS: The aortic valve (AV) neocuspidization (Ozaki procedure) is a novel surgical technique for AV disease that preserves the natural motion and cardiodynamics of the aortic root. In this study, we sought to evaluate, by 4D-flow magnetic resonance imaging, the aortic blood flow characteristics after AV neocuspidization in paediatric patients. METHODS AND RESULTS: Aortic root and ascending aorta haemodynamics were evaluated in a population of patients treated with the Ozaki procedure; results were compared with those of a group of patients operated with the Ross technique. Cardiovascular magnetic resonance studies were performed at 1.5 T using a 4D flow-sensitive sequence acquired with retrospective electrocardiogram-gating and respiratory navigator. Post-processing of 4D-flow analysis was performed to calculate flow eccentricity and wall shear stress. Twenty children were included in this study, 10 after Ozaki and 10 after Ross procedure. Median age at surgery was 10.7 years (range 3.9-16.5 years). No significant differences were observed in wall shear stress values measured at the level of the proximal ascending aorta between the two groups. The analysis of flow patterns showed no clear association between eccentric flow and the procedure performed. The Ozaki group showed just a slightly increased transvalvular maximum velocity. CONCLUSION: Proximal aorta flow dynamics of children treated with the Ozaki and the Ross procedure are comparable. Similarly to the Ross, Ozaki technique restores a physiological laminar flow pattern in the short-term follow-up, with the advantage of not inducing a bivalvular disease, although further studies are warranted to evaluate its long-term results.

'The bubble heart': an unusual natural history told by multimodality imaging- a case report.

BACKGROUND: Intracardiac thrombosis is a relatively common pathological condition. Often, it is diagnosed at echocardiography during the subacute or chronic phase. In the very acute phase, tissue composition can make thrombus appearance very different from that usually seen. Fresh thrombosis has been previously found also in peripartum cardiomyopathy (PPC), but with imaging features different from our case. CASE SUMMARY: A 27-year-old woman was referred to our hospital for PPC, with echocardiographic finding of intraventricular masses, resembling big bubbles. Cardiac magnetic resonance (CMR) allowed definitively diagnosing intracardiac 'very acute' thrombosis, which is rarely detected. DISCUSSION: Our case provides a practical lesson about management of an unusual presentation of a common problem. When early echocardiography does not allow making a certain diagnosis, CMR can be helpful and decisive, due to its unique ability to provide characterization of intracardiac masses.

Dynamic contrast-enhanced magnetic resonance lymphangiography in pediatric patients with central lymphatic system disorders.

Central conducting lymphatics (CCLs) disorders represent a broad spectrum of clinical entities ranging from self-limiting traumatic leaks treated by conservative strategies, to complex lymphatic circulation abnormalities that are progressive and unresponsive to currently available treatments. Dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) performed by intranodal injection of gadolinium-based contrast material is a recently developed technique which allows a minimally invasive evaluation of the CCL abnormalities providing a dynamic assessment of lymph flow and its pathways. In our institution, DCMRL is performed after bilateral cannulation of inguinal lymph nodes, using a MR protocol which includes volumetric 3D T2-SPACE (sampling perfection with application-optimized contrasts using different flip-angle evolution) and free-breathing respiratory navigated sequence and TWIST (time-resolved angiography with Interleaved stochastic trajectories) MR angiography sequence, during intranodal injection of paramagnetic contrast medium. Although DCMRL applications in clinical practice are still improving, a minimally invasive assessment of lymphatic pathways is particularly important both in pediatric patients with primitive lymphatic system disorders and in children with complex congenital heart disease associated with CCL impairment.

Dual-source computed tomography coronary artery imaging in children.

Computed tomography (CT) has a well-established diagnostic role in the assessment of coronary arteries in adults. However, its application in a pediatric setting is still limited and often impaired by several technical issues, such as high heart rates, poor patient cooperation, and radiation dose exposure. Nonetheless, CT is becoming crucial in the noninvasive approach of children affected by coronary abnormalities and congenital heart disease. In some circumstances, CT might be preferred to other noninvasive techniques such as echocardiography and MRI for its lack of acoustic window influence, shorter acquisition time, and high spatial resolution. The introduction of dual-source CT has expanded the role of CT in the evaluation of pediatric cardiovascular anatomy and pathology. Furthermore, technical advances in the optimization of low-dose protocols represent an attractive innovation. Dual-source CT can play a key role in several clinical settings in children, namely in the evaluation of children with suspected congenital coronary artery anomalies, both isolated and in association with congenital heart disease. Moreover, it can be used to assess acquired coronary artery abnormalities, as in children with Kawasaki disease and after surgical manipulation, especially in case of transposition of the great arteries treated with arterial switch operation and in case of coronary re-implantation.

Role of cardiovascular magnetic resonance end-systolic 3D-SSFP sequence in repaired tetralogy of Fallot patients eligible for transcatheter pulmonary valve implantation.

To evaluate the usefulness of cardiovascular magnetic resonance (CMR) 3D steady state free precession (SSFP) sequence acquired at end-systole (ES) in repaired Tetralogy of Fallot (rToF) patients eligible for percutaneous pulmonary valve implantation (PPVI). Between 2012 and 2018, 78 rToF patients were selected for pulmonary valve replacement (PVR) according to CMR criteria. CMR protocol included 3D-SSFP sequence used to assess the right ventricle outflow tract (RVOT) diameters at three levels (pulmonary valve remnant, mid-portion, bifurcation) in mid-diastole (MD) or ES, RVOT length and coronary artery anatomy. In 20 rToF patients without indications for PVR (controls), 3D SSFP sequence was acquired at both cardiac phases (MD and ES) to evaluate RVOT dimension throughout the cardiac cycle. Invasive balloon sizing was recorded in patients undergoing PPVI. The 3D-SSFP sequence was performed in MD on 39 patients and in ES on other 39, of whom 26 patients met the criteria for PPVI. The latter was unsuccessful in ten patients (38%), mainly due (80% of cases) to significant size discrepancy at PV remnant and bifurcation levels (p = 0.019 and 0.037 respectively) between the measurements by 3D-SSFP in MD and those by the balloon size in systole. Significant RVOT size difference between MD and ES was present at mid-portion and bifurcation levels in the PVR candidate group, and at all three-levels in the control group (all p < 0.001). ES 3D-SSFP sequence is able to quantify RVOT dilation in rToF patients at its maximum expansion, thus improving selection of PPVI candidates.

Results of Late Gadolinium Enhancement in Children Affected by Dilated Cardiomyopathy.

BACKGROUND: Little is known about the clinical value of late gadolinium enhancement (LGE), in children affected by dilated cardiomyopathy (DCM). MATERIALS AND METHODS: We retrospectively evaluated 15 patients (8 ± 6 years, 6 males) with diagnosis of DCM who underwent cardiac magnetic resonance since 2014. All scans were performed with a 1.5 T system (Aera, Siemens). Study protocol included cine steady-state free precession sequences, followed by administration of 0.2 mmol/kg of gadolinium-based contrast agent. Inversion recovery Turbo Flash sequences, in the same position of cine images, were acquired 10-15 min after the injection of contrast agent, in order to assess the presence of LGE. The latter was considered positive with a signal intensity >6 SD from normal myocardial tissue. Indexed end-diastolic volume (EDVi) and end-systolic volume (ESVi), and left ventricle (LV) ejection fraction (EF) were calculated by using dedicated software on off-line workstation. Global longitudinal strain and diastolic function were evaluated by echocardiography. Clinical follow-up, including death, transplant, and listing for heart transplant [major adverse cardiac events (MACE)], were evaluated. Patients were divided into two different subgroups: negative (Group A) and positive (Group B) for presence of LGE. Statistical analysis was performed by using Mann-Whitney U test (p < 0.05 considered as statistically significant). RESULTS: Seven patients (47%) showed LGE. A global diffuse subendocardial pattern was evident in all patients presenting LGE (7/7, 100%). The following main LV indexes were observed in the two subgroups. Group A: EDVi = 96 ± 33 ml, ESVi = 56 ± 29 ml, LV EF = 45 ± 10%, global longitudinal strain = -16 ± 5%, E/e' ratio = 10 ± 3, MACE = 1. Group B: EDVi = 130 ± 60 ml, ESVi = 89 ± 43 ml, LV EF = 31 ± 6%, global longitudinal strain = -13 ± 4%, E/e' ratio = 9 ± 3, MACE = 3. There was no statistically significant difference between the two groups, in terms of EDVi (p: 0.2), ESVi (p: 0.2), and E/e' ratio (0.9), whereas a significant difference of LV EF, presence of significative mitral regurgitation, and global longitudinal strain were observed (respectively, p: 0.03, p: 0.009, and p: 0.03). CONCLUSION: In our population of children with DCM, LGE shows a global diffuse subendocardial pattern. Presence of LGE seems to play a role in these patients determining a worst global systolic function.

Multicenter review: role of cardiovascular magnetic resonance in diagnostic evaluation, pre-procedural planning and follow-up for patients with congenital heart disease.

The number of patients with congenital heart disease (CHD) is rapidly increasing in the adult population, mainly due to the improved long-term survival. Serial follow-up with cardiac magnetic resonance imaging (CMR) is very appealing due to its non-invasive nature. CMR exam is able to provide specific information about cardiac function, hemodynamics, anatomy and tissue characterization unlikely achievable by other diagnostic techniques. CMR in CHD plays a role both in early diagnosis and in post-operative follow-up. Black Blood T1 weighted sequences are used to acquire morphological information. Cine Steady State Free Precession sequences are mainly used to provide data about cardiac function and kinesis. Hemodynamic assessment is routinely performed using phase contrast sequences, which provide reliable information concerning vessel flow pattern, cardiac output and intracardiac shunts. Magnetic Resonance Angiography (MRA) and 3D coronary MRA of the whole thorax can provide detailed morphological information regarding great vessels and proximal coronary arteries. Presence of late gadolinium enhancement suggesting myocardial macroscopic fibrosis seems to play a prognostic and diagnostic role even in this field.

Concordance of angiographic and electrocardiographic indexes of microvascular obstruction: myocardial haemorrhage role.

BACKGROUND: Angiographic and electrocardiographic (ECG) indexes of microvascular obstruction (MVO) have been described. We aimed at assessing by cardiac magnetic resonance (CMR) anatomical features underlying concordance between them. METHODS: Forty-one patients were enrolled. Patients presented with neither angiographic nor ECG indexes of MVO (without MVO) (44%), with either angiographic or ECG indexes of MVO (discordant with MVO) (22%) or with both angiographic and ECG indexes of MVO (concordant with MVO) (34%). All patients underwent in-hospital CMR. Echocardiographic data obtained after 6 months were compared with those obtained in hospital. RESULTS: Concordant patients with MVO had larger infarct size, lower myocardial salvage index and higher rate of myocardial haemorrhage (all assessed by CMR) [33% (25-41%), 15% (10-29%) and 88%, respectively] as compared with patients without MVO [12% (9-16%), 66% (52-79%) and 0%; Bonferroni-adjusted P < 0.001, Bonferroni-adjusted P < 0.001 and P < 0.001, respectively], or with discordant ones [25% (21-39%), 35% (20-48%) and 7%; Bonferroni-adjusted P = 0.03, Bonferroni-adjusted P = 0.002 and P = 0.04, respectively]. After 6 months, ejection fraction significantly decreased in concordant patients with MVO (P < 0.001) without significant changes in the other groups. CONCLUSIONS: Concordance of angiographic and ECG indexes of MVO reflects more severe myocardial damage translating into unfavourable left ventricular remodelling.

Electrocardiographic findings and myocardial damage in acute myocarditis detected by cardiac magnetic resonance.

Delayed-contrast-enhancement (DCE) magnetic resonance imaging (MRI) can identify areas of myocardial damage in patients with acute myocarditis (AM). The aim of this study was to assess the electrocardiographic findings in AM diagnosed by DCE-MRI. Eighty-one patients (72 men, 35 ± 13 years) with AM were prospectively enrolled. All of them underwent MRI and 12-lead-ECG recordings. In the admission electrocardiogram (ECG 1), as well as in that obtained 48 h later (ECG 2), the following parameters were analyzed: rhythm, PR, QRS, and QTc-intervals, intraventricular conduction, abnormal Q waves, ST segment elevation, and T wave inversion. On admission, 77 patients (95%) were in sinus rhythm, while four patients (6%) manifested severe arrhythmias. No difference between ECG 1 and ECG 2 was observed regarding abnormal Q waves, PR, QRS, and QTc-intervals. Electrocardiogram 1 was normal in 26 patients (32%, normal ECG group), and abnormal in 55 patients (68%, abnormal ECG group). ST elevation was found in 46 patients (57%), inverted T wave in seven patients (9%) and left bundle branch block (LBBB) in two patients (3%). Areas of DCE suggesting AM were found in each patient. No relationship concerning the location of the involved region (s) was found between ECG (leads with ST/T abnormalities) and MRI (areas showing DCE). The ECG in AM can either be normal or reflect abnormalities including arrhythmias, LBBB, ST segment elevation, and T wave inversion. The location of myocardial involvement deduced on the basis of ECG leads showing ST/T changes is not in close relationship with the areas of ventricular damage detected by MRI.

Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation.

The synthesis of a small library of resorcylic acid lactones and evaluation of their biological properties as kinase inhibitors is described. Within the series E-enones were found more active than corresponding Z-enones as inhibitors of a subset of kinases containing a conserved cysteine. Replacement of the enone moiety with a ß-haloketone group led to compounds with an interesting kinase selectivity profile and also antiproliferative activity against Jurkat cells. An E-enone derivative also showed activity against capillary tube formation based on a co-culture of primary human umbilical cord endothelial cells (HUVECs) and vascular smooth muscle cells (vSMCs).

Access to resorcylic acid lactones via phosphonate based intramolecular olefination.

An approach to resorcylic acid lactones is described, exploiting an intramolecular olefination reaction for the generation of the 14-membered macrolactone. The synthetic route gave zearalenone precursors, and the preparations of other RAL analogues, trans- and cis-resorcylides are included, the latter being prepared by photoisomerization of the trans-isomer. ß-Haloketone derivatives were also prepared in a highly stereoselective manner by conjugate addition of chloride or bromide to the E-enone using boron trichloride and boron tribromide, respectively.

Highly stereoselective de novo synthesis of L-hexoses.

An efficient and general de novo synthetic route to enantiomerically pure L-hexoses has been accomplished starting from the heterocyclic homologating agent 5,6-dihydro-1,4-dithiin-2-yl[(4-methoxybenzyl)oxy]methane and methyl alpha,beta-isopropylidene-L-glycerate. The sugar scaffold was constructed by an acid-catalyzed domino reaction, which enabled selective preparation of either methyl 2,3-dideoxy-alpha-L-threo-hex-2-enopyranosides or 1,6-anhydro-2,3-dideoxy-beta-L-threo-hex-2-enopyranose as key intermediates. The subsequent double bond functionalization by syn or anti dihydroxylation reactions allowed introduction of the remaining stereogenic centers, leading to desired orthogonally protected L-hexopyranosides with a high degree of diastereoselectivity and with very good overall yields. These and previous results (based on the use of the corresponding L-erythro epimers) contribute to make our approach general and place it among the few methods able to synthesize the whole series of the rare L-hexoses.

Carnitine conjugate of nipecotic acid: a new example of dual prodrug.

As a novel example of improved entry of poorly delivered drugs into the brain by means of nutrient conjugates, L-carnitine was conjugated to nipecotic acid and the capacity to antagonize PTZ-induced convulsions of this novel entity was evaluated.

Rapid access to 1,6-anhydro-beta-L-hexopyranose derivatives via domino reaction: synthesis of L-allose and L-glucose.

An expeditious and efficient synthesis of 1,6-anhydro-beta-L-hexopyranosyl derivatives 3 as valuable building blocks for the preparation of L-sugars is herein reported. This route relies upon the use of a domino reaction involving five synthetic steps from the 5,6-dihydro-1,4-dithiin 4. As 1,6-anhydro derivatives 3 are obtained, dithioethylene bridge removal and double-bond dihydroxylation give access to protected L-allose and L-glucose in stereoselective fashion and high yields.

A versatile route to L-hexoses: synthesis of L-mannose and L-altrose.

[reaction: see text] An efficient route for the synthesis of orthogonally protected l-sugars has been opened up, starting from the heterocyclic homologating agent 1 and 2,3-O-isopropylidene-l-glyceraldehyde (2). Our synthetic path enables the synthesis of a 2,3-unsaturated-l-pyranoside, which can be suitably functionalized to afford the desired l-hexoses. In this paper, we report the synthesis of l-manno- and l-altro-pyranosides. Moreover, this strategy may be used to prepare all eight sugars and their derivatives in either enantiomeric form.