Synthesis and structure-activity relationships of new 9-N-alkyl derivatives of 9(S)-erythromycylamine

A series of new 9-N-alkyl derivatives of 9(S)-erythromycylamine has been synthesized by reductive alkylation of erythromycylamine with aliphatic aldehydes and sodium cyanoborohydride. Alternative syntheses employing hydrogenation methods have also been developed. These new 9-N-alkyl derivatives possess excellent antimicrobial activity in vitro and in vivo, especially when administered orally to treat experimental infections in mice. From structure-activity studies, 9-N-(1-propyl)erythromycylamine (LY281389) was selected as the most efficacious derivative. These methods have also been extended to the synthesis of some 9-N,N-dialkyl derivatives of erythromycylamine.     

Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives

A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78 approximately 6.25 micrograms/ml) as well as Mycoplasma species (MIC range of 0.39 approximately 6.25 micrograms/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks. One of these derivatives, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin or EL-870) was selected for development as a therapeutic agent for pasteurellosis in calves and pigs.     

Structure-activity studies of 20-deoxo-20-amino derivatives of tylosin-related macrolides

Reductive amination of the C-20 aldehyde group of tylosin and related macrolides yielded a large series of derivatives with potentially useful antibiotic properties. Evaluation of these new compounds was conducted on the basis of: 1) Broad antimicrobial spectrum in vitro, with particular emphasis on inhibition of Pasteurella multocida and Pasteurella haemolytica; 2) in vivo efficacy, especially when given orally, against P. multocida in experimental infections in chicks; and 3) bioavailability after oral administration to laboratory animals. The most useful activity was found within a series of derivatives produced by reductive amination of desmycosin with secondary amines.     

Scoping Meta‐Review: Introducing a New Methodology

For researchers, policymakers, and practitioners facing a new field, undertaking a systematic review can typically present a challenge due to the enormous number of relevant papers. A scoping review is a method suggested for addressing this dilemma; however, scoping reviews present their own challenges. This paper introduces the “scoping meta‐review” (SMR) for expanding current methodologies and is based on our experiences in mapping the field of consumer engagement in healthcare. During this process, we developed the novel SMR method. An SMR combines aspects of a scoping review and a meta‐review to establish an evidence‐based map of a field. Similar to a scoping review, an SMR offers a practical and flexible methodology. However, unlike in a traditional scoping review, only systematic reviews are included. Stages of the SMR include: undertaking a preliminary nonsystematic review; building a search strategy; interrogating academic literature databases; classifying and excluding studies based on titles and abstracts; saving the refined database of references; revising the search strategy; selecting and reviewing the full text papers; and thematically analyzing the selected texts and writing the report. The main benefit of an SMR is to map a new field based on high‐level evidence provided by systematic reviews.     

A comparison between dual axis rotational coronary angiography and conventional coronary angiography

Background: Coronary angiography remains the gold standard for the investigation of coronary artery disease, and is carried out in multiple, predefined stationary views, at different angulations around the patient, for both left and right coronary arteries. Dual axis rotational coronary angiography (DARA) is an alternative technique wherein the c‐arm rotates around the patient in a preprogrammed single acquisition, exposing the entire coronary artery at different angulations. The DARA system has been recently installed in the Cardiac Catheterisation Suite at Mater Dei Hospital, Malta, where a monoplane and a biplane machine are available. This study was carried out in order to compare DARA with conventional single and biplane coronary imaging, with respect to radiation dose, contrast loads, and procedure time. Methods: This study was carried out over the period from September to December 2010. Four hundred sixty‐three patients were studied. Patients referred for the investigation of native coronary anatomy, for whatever indication, were consented and included, and randomly assigned to one of four groups depending on which machine and modality was used: monoplane conventional, monoplane DARA, biplane conventional, and biplane DARA. Results: DARA was statistically significantly superior in dose area product, fluoroscopy time, amount of contrast used, and procedure time. These reductions ranged between 12 (contrast used) and 71% (procedure time). Conclusions: The advantages of such systems are obvious to both patient and healthcare provider, and DARA may prove to be an important and useful tool in the refinement of diagnostic coronary angiography by reducing patient contrast and radiation doses and reducing procedure time. © 2012 Wiley Periodicals, Inc.     

Ruptured anterior communicating artery aneurysm. Therapeutic options in 119 consecutive cases

BACKGROUND AND PURPOSE: The respective roles of endovascular and surgical treatment must be clearly defined in the management of ruptured anterior communicating artery (AcoA) aneurysm. The aim of our study was to report our results, using the aneurysm direction as the main morphological argument to choose between microsurgery and endovascular embolization. Morbidity and mortality, causes of unfavorable outcome and morphological results were also assessed. PATIENTS AND METHODS: Our prospective study included 119 patients: 89 treated by microsurgery and 30 undergoing embolization with Guglielmi Detachable Coils (GDC). When the aneurysm had an anterior direction (fundus of the aneurysm in front of the pericallosal arteries), we attempted microsurgery. If the fundus of the aneurysm was behind the pericallosal arteries, we selected the most adapted procedure after discussion with the neurovascular team, taking into account the physiological status, treatment risk and neck size. Preoperative status of the patients was assessed according to the Hunt and Hess (HH) classification. Cerebral CT-scan and angiograms were routinely performed after treatment to determine causes of unfavorable outcome (GOS>1) and the morphological results. RESULT: Overall clinical outcome was excellent (GOS1) for 63.0% of patients, good (GOS2) for 10.1%, fair (GOS3) for 13.4%, poor (GOS4) for 2.5%. The mortality rate was 10.9%. Among the 82 patients in good preoperative grade (HHIII), 8 (21.6%) achieved an excellent outcome. However permanent morbidity or death occurred in 15 patients (78.4%). Permanent disability and death were related to initial subarachnoid hemorrhage and were observed 21.3% of patients in the microsurgical group and 30.0% in the endovascular group [Fisher's Exact Test; p=0.33]. Procedure-related permanent disability and death rates were 9.0% for the microsurgical group and 23.3% for the endovascular group (p=0.06) respectively. In the microsurgical group, the only morphologic characteristic which significantly correlated with the occurrence of vessel occlusion was the fundus direction (p=0.03). The difference between endovascular and microsurgical procedures in the achievement of complete occlusion was considered significant (p=0.04). CONCLUSION: In our experience, the direction of the aneurysm was the main morphological criterion in choosing between microsurgery or endovascular procedure for the treatment of AcoA aneurysm. We propose that microsurgical clipping should be preferred for AcoA aneurysms with anterior direction, and depending on morphological criteria, endovascular packing for those with posterior direction.     

New phenotypic diversity associated with the mitochondrial tRNA(SerUCN) gene mutation

We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.     

Treatment of anterior communicating artery aneurysms: complementary aspects of microsurgical and endovascular procedures

OBJECT: Endovascular and surgical treatment must be clearly defined in the management of anterior communicating artery (ACoA) aneurysms. In this study the authors report their recent experience in using a combined surgical and endovascular team approach for ACoA aneurysms, and compare these results with those obtained during an earlier period in which surgical treatment was used alone. Morbidity and mortality rates, causes of unfavorable outcomes, and morphological results were also assessed. METHODS: The prospective study included 223 patients who were divided into three groups: Group A (83 microsurgically treated patients, 1990-1995); Group B (103 microsurgically treated patients, 1996-2000); and Group C (37 patients treated with Guglielmi Detachable Coil [GDC] embolization, 1996-2000). Depending on the direction in which the aneurysm fundus projected, the authors attempted to apply microsurgical treatment to Type 1 aneurysms (located in front of the axis formed by the pericallosal arteries). They proposed the most adapted procedure for Type 2 aneurysms (located behind the axis of the pericallosal arteries) after discussion with the neurovascular team, depending on the physiological status of the patient, the treatment risk, and the size of the aneurysm neck. In accordance with the classification of Hunt and Hess, the authors designated those patients with unruptured aneurysms (Grade 0) and some patients with ruptured aneurysms (Grades I-III) as having good preoperative grades. Patients with Grade IV or V hemorrhages were designated as having poor preoperative grades. By performing routine angiography and computerized tomography scanning, the causes of unfavorable outcome (Glasgow Outcome Scale [GOS] score < 5) and the morphological results (complete or incomplete occlusion) were analyzed. Overall, the clinical outcome was excellent (GOS Score 5) in 65% of patients, good (GOS Score 4) in 9.4%, fair (GOS Score 3) in 11.6%, poor (GOS Score 2) in 3.6%, and fatal in 10.3% (GOS Score 1). Among 166 patients in good preoperative grades, an excellent outcome was observed in 134 patients (80.7%). The combined permanent morbidity and mortality rate accounted for up to 19.3% of patients. The rates of permanent morbidity and death that were related to the initial subarachnoid hemorrhage were 6.2 and 1.5% for Group A, 6.6 and 1.3% for Group B, and 4 and 4% for Group C, respectively. The rates of permanent morbidity and death that were related to the procedure were 15.4 and 1.5% for Group A, 3.9 and 0% for Group B, and 8 and 8% for Group C, respectively. When microsurgical periods were compared, the rate of permanent morbidity or death related to microsurgical complications decreased significantly (Group A, 11 patients [16.9%] and Group B, three patients [3.9%]); Fisher exact test, p = 0.011) from the period of 1990 to 1995 to the period of 1996 to 2000. The combined rate of morbidity and mortality that was related to the endovascular procedure (16%) explained the nonsignificance of the different rates of procedural complications for the two periods, despite the significant decrease in the number of microsurgical complications. Among 57 patients in poor preoperative grade, an excellent outcome was observed in 11 patients (19.3%); however, permanent morbidity (GOS Scores 2-4) or death (GOS Score 1) occurred in 46 patients (80.7%). With regard to the correlation between vessel occlusion (the primary microsurgical complication) and the morphological characteristics of aneurysms, only the direction in which the fundus projected appeared significant as a risk factor for the microsurgically treated groups (Fisher exact test: Group A, p = 0.03; Group B, p = 0.002). The difference between endovascular and microsurgical procedures in the achievement of complete occlusion was considered significant (chi2 = 6.13, p = 0.01). CONCLUSIONS: The direction in which the fundus projects was chosen as the morphological criterion between endovascular and surgical methods. The authors propose that microsurgical clip application should be the preferred option in the treatment of ACoA aneurysms with anteriorly directed fundi and that endovascular packing be selected for those lesions with posteriorly directed fundi, depending on morphological criteria.