A new class of selective myocardial calcium channel modulators. 2. Role of the acetal chain in oxadiazol-3-one derivatives

In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC(50) = 0.04 microM), which is 20 times more active than diltiazem (EC(50) = 0.79 microM), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.     

Left atrial compression with acute heart failure caused by esophageal bolus

We report a case of left atrial extrinsic compression caused by an esophageal food bolus in a patient presenting with acute heart failure. Transthoracic echocardiography along with contrast‐enhanced CT showed evidence of esophageal dilation producing left atrial compression. Esophageal endoscopy and fragmentation of the bolus, allowing the accumulated food to descend into the stomach, produced a rapid improvement of hemodynamic and clinical status. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46 :259–261, 2018     

N-Acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity

OBJECTIVES: We performed a study to assess the efficacy of fenoldopam mesylate (a specific agonist of the dopamine-1 receptor) as compared with N-acetylcysteine (NAC) in preventing contrast agent-associated nephrotoxicity (CAN). BACKGROUND: Prophylactic administration of NAC, along with hydration, prevents CAN in patients with chronic renal insufficiency who are undergoing contrast media administration. Preliminary data support the hypothesis that fenoldopam might be as effective as NAC. METHODS: One hundred ninety-two consecutive patients with chronic renal insufficiency, referred to our institution for coronary and/or peripheral procedures, were assigned randomly to receive 0.45% saline intravenously and NAC (1,200 mg orally twice daily; NAC group; n = 97) or fenoldopam (0.10 microg/kg/min; fenoldopam group; n = 95) before and after a nonionic, iso-osmolality contrast dye administration. RESULTS: Baseline creatinine levels were similar in the two groups: NAC group = 1.72 mg/dl (interquartile range, 1.55 to 1.90 mg/dl) and fenoldopam group = 1.75 mg/dl (interquartile range, 1.62 to 2.01 mg/dl) (p = 0.17). An increase of at least 0.5 mg/dl of the creatinine concentration 48 h after the procedure occurred in 4 of 97 patients (4.1%) in the NAC group and in 13 of 95 patients (13.7%) in the fenoldopam group (p = 0.019; odds ratio 0.27; 95% confidence interval 0.08 to 0.85). The amount of contrast media administration was similar in the two groups (NAC group = 160 +/- 82 ml; fenoldopam group = 168 +/- 104 ml; p = 0.54). CONCLUSIONS: N-acetylcysteine seems to be more effective than fenoldopam in preventing CAN.     

Usefulness of three-dimensional transthoracic echocardiography in particular clinical settings: a case of aorto-cavitary fistula in periprosthetic aortic valve abscess

Prosthetic valve endocarditis (PVE) due to staphylococcus aureus is associated with high morbidity and mortality. Paravalvular abscess formation is a common complication of PVE at the aortic position, but fistula formation is rarely seen. The transesophageal echocardiography is the "gold-standard" exam to detect PVE. We present a case of a 69-year-old patient with prosthetic aortic valve endocarditis, paravalvular abscess, and fistula in right atrium, where the diagnosis was made with three-dimensional transthoracic echocardiography, without transesophageal evaluation.     

Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization

Colocalization of dopamine D1 (D1R) and D3 receptors (D3R) in specific neuronal populations suggests that their functional cross-talk might involve direct interactions. Here we report that the D1R coimmunoprecipitates with the D3R from striatal protein preparations, suggesting that they are clustered together in this region. Using bioluminescence resonance energy transfer (BRET(2)), we further suggest the existence of a physical interaction between D1R and D3R. Tagged D1R and D3R cotransfected in human embryonic kidney (HEK) 293 cells generated a significant BRET(2) signal that was insensitive to agonist stimulation, suggesting that they form a constitutive heterodimer. D1R and D3R regulate adenylyl cyclase (AC) in opposite ways. In HEK 293 cells coexpressing D1R and D3R, dopamine stimulated AC with higher potency and displaced [3H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) binding with higher affinity than in cells expressing the D1R. In HEK 293 cells individually expressing D1R or D3R, agonist stimulation induces internalization of D1R but not of D3R. Heterodimerization with D3R abolishes agonist-induced D1R cytoplasmic sequestration induced by selective D1R agonists and enables internalization of the D1R/D3R complex in response to the paired stimulation of both D1R and D3R. This mechanism involves beta-arrestin binding because it was blocked by mutant beta-arrestinV53D. These data suggest that as a result of dimerization, the D3R is switched to the desensitization mechanisms typical of the D1R. These data give a novel insight into how D1R and D3R may function in an integrated way, providing a molecular mechanism by which to converge D1R- and D3R-related dysfunctions.     

Medial thigh lift in post-bariatric patients: Our encouraging experience

Background: A high rate of postoperative complications following inner thigh lift is reported in the medical literature. The authors present the results of a study on the validity of inner thigh contouring, with liposuction and concomitant skin excision, in postbariatric patients.

Methods: This study examined the charts of 46 postbariatric female patients, who underwent medial thigh lift with a ‘T’ scar technique and concomitant liposuction, between February 2010 and February 2013. Complications were recorded. A questionnaire was administered to the patients at the 1-year follow-up visit. Preoperative and 1-year postoperative photographs were compared, superimposed, and analysed.

Results: This study did not observe major systemic complications, haematoma, seroma, infection, skin necrosis, lymphoceles, or lymphoedema. Minor complications were three cases of wound dehiscence and two cases of deepithelialisation. At the 1-year follow-up visit, caudal scar migration, genital distortion, recurrent ptosis, or deformity of the inner thigh contour were not observed. Questionnaires and a comparison of pre- and 1-year postoperative pictures showed encouraging results.

Conclusions: The medial thigh lift technique described and assessed in this article is a straightforward surgical procedure, with considerable functional and aesthetic results. Liposuction, early mobilisation, and appropriate postoperative management are pivotal to reduce postoperative downtime and complications.     

Elective palliative resection of incurable stage IV colorectal cancer: Who really benefits from it?

Purpose  

Despite the encouraging results of chemotherapy in patients affected by incurable colorectal cancer (CRC), surgical resection of a primitive tumor is still a common approach worldwide. The identification of prognostic factors related to short survival (<6 months) may allow excluding from resective surgery those who may not benefit from it.