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In atrial fibrillation the correct identification of both presence and location of rotors during the ablation procedure could support the physician to optimize therapy administration. In this study we developed a tool that allows testing the capability of mapping catheters of detecting AF drivers with different shapes and in different acquisition conditions. Wave propagation was obtained using a monodomain implementation and a modified Courtemanche model. Two commercial catheters were simulated (Advisor™ HD Grid and PentaRay®). Our framework allowed the acquisition of the signal in unipolar mode at and to assess the effect of the influence of catheter inter-electrode spacing, coverage and endocardium-LA wall distance for rotor detection. In contact with the wall and within 1 mm distance from the real core all the configurations allowed a correct detection of the rotor, irrespective of geometry, coverage and inter-electrode distance. Increasing the interelectrode distance causes the incapability of rotor detection at a closer distance from the LA wall in the HD grid. The tool was effective in assessing how catheter geometry and specific parameters affect its capability to detect rotors. In the future, other catheter morphologies and different design parameters and acquisition conditions will be investigated.

The aim of our work consists in developing a new model of the human ventricular cardiomyocyte, based on the O'Hara-Rudy model (ORd), to improve, in particular, the action potential duration (APD) dependence on the extracellular Ca2+ concentration (Cao). Moreover, the new model reproduces all the available experimental data on APD rate dependence, APD restitution, drug block effects, etc., when the experimental extracellular ionic concentrations are carefully reproduced in simulationsThe main differences between our and the ORd model are: a novel Markovian formulation for the L-type Ca2+ current; the Markovian rapid delayed rectifier K+ current formulation published by Li et al.; a new formulation of the Ca2+ release from the sarcoplasmic reticulum. Several model parameters were modifiedOur BS (Bartolucci-Severi) model successfully improved the ORd, one of the most detailed, used and influent models in computational cardiology, by reproducing the APD-Cao relationship while keeping all the original model features tested in the appropriate experimentally-matched conditions. Furthermore, the BS was suitability as baseline for the generation of in silico populations of models and for reproducing cardiac abnormalities such as early afterdepolarizations.

Laparoscopic treatment of early-stage endometrial cancer is the gold standard to reduce perioperative morbidity. Obesity is a well-known risk factor for endometrial cancer and anesthesiological and surgical complications. The authors' aim was to examine the effect of body mass index (BMI) on perioperative parameters and complications in laparoscopically-treated patients with endometrial cancer.A consecutive series of patients affected by endometrial cancer and their demographic and clinicopathological data were collected. Patients were divided in 41 non-obese (BMIor= 29.9) and 34 obese (BMIor= 30) groups. All patients had been preoperatively evaluated with hysteroscopic procedures and toraco-abdominal computed tomography (CT) and had been submitted to laparoscopic radical hysterectomy according to Querleu-Morrow, pelvic lymphadenectomy, peritoneal washing, and bilateral adnexectomy.There was no statistically significant difference in blood loss, number of lymph nodes removed, and hospital stay between the groups, but there was a trend towards a lengthening of surgical time in the obese women. There were no major intraoperative and postoperative complications.This study demonstrates that laparoscopic approach is feasible and safe in obese women evaluating the anesthesiological risk.

The aims of this work were the optimization of the IKr model, based on the Luo-Rudy (LRd) formulation by fitting it to IKr recorded as E4031-sensitive current (IE4031) under Action Potential clamp and the validation of the optimized model by testing its suitability to replace native IKr under Dynamic Clamp conditions. We found the experimental IE4031 very different from the IKr based on the LRd model. We therefore looked for an IKr formulation which better fit our experimental data. By solving a minimization problem we found an 'optimized' formulation of the IKr model. The optimized model was validated by using the dynamic clamp technique: we considered the AP traces in control conditions, under IKr block, after injection of the modeled LRd IKr and after injection of the optimized modeled IKr. Dynamic clamp experiments showed that the LRd IKr shortens too much the action potential while our model brings back the AP closer the control AP morphology and duration. © 2013 CCAL.

Natural and synthetic carbamates act as pseudo-irreversible inhibitors of AChE (acetylcholinesterase) as well as BChE (butyrylcholinesterase), two enzymes involved in neuronal function as well as in the development and progression of AD (Alzheimer's disease). The AChE mode of action is characterized by a rapid carbamoylation of the active-site Ser(200) with release of a leaving group followed by a slow regeneration of enzyme action due to subsequent decarbamoylation. The experimental AD therapeutic bisnorcymserine, a synthetic carbamate, shows an interesting activity and selectivity for BChE, and its clinical development is currently being pursued. We undertook detailed kinetic studies on the activity of the carbamate bisnorcymserine with Tc (Torpedo californica) AChE and, on the basis of the results, crystallized the complex between TcAChE and bisnorcymserine. The X-ray crystal structure showed only the leaving group, bisnoreseroline, trapped at the bottom of the aromatic enzyme gorge. Specifically, bisnoreseroline interacts in a non-covalent way with Ser(200) and His(440), disrupting the existing interactions within the catalytic triad, and it stacks with Trp(84) at the bottom of the gorge, giving rise to an unprecedented hydrogen-bonding contact. These interactions point to a dominant reversible inhibition mechanism attributable to the leaving group, bisnoreseroline, as revealed by kinetic analysis.

N-Piperidinopropyl-galanthamine (2) and N-saccharinohexyl-galanthamine (3) were used to investigate interaction sites along the active site gorge of Torpedo californica actylcholinesterase (TcAChE). The crystal structure of TcAChE-2 solved at 2.3 A showed that the N-piperidinopropyl group in 2 is not stretched along the gorge but is folded over the galanthamine moiety. This result was unexpected because the three carbon alkyl chain is just long enough for the bulky piperidine group to be placed above the bottleneck (Tyr121, Phe330) midway down the gorge. The crystal structure of TcAChE-3 at 2.2 A confirmed that a dual interaction with the sites at the bottom, and at the entrance of the gorge, enhances inhibitory activity: a chain of six carbon atoms has, in this class of derivatives, the correct length for optimal interactions with the peripheral anionic site (PAS).

Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.

About 40% of patients with Crohns disease (CD) have a perianal involvement. Despite the recent introduction of anti-TNF antibody, this therapy has uncertain long-term results and surgery still remains a major treatment option.This study relates our experience in surgical management of perianal CD without anti-TNF treatment. From July 92 to February 02, 37 patients with perianal Crohns disease were treated, 43 underwent local operations or faecal diversion for fistulas and/or abscesses. Patients not requiring surgery or in therapy with anti-TNF. were excluded from the study. We analysed the outcome of surgical treatment for perianal CD.Male to female ratio was 1:0.6, median age was 36,9 years (range 17-62). Perianal disease included 32 fistulas (16 trans-sphincteric, 2 superficial, 2 ano-vaginal, 10 multiple and complex, 2 horseshoe) and 7 abscesses (5 perianal, 2 ischio-rectal). Local surgery included 1 abscess drainage, 5 abscess drainage and fistula incision with seton insertion, 2 fistulotomy, 9 partial fistulectomy and seton insertion. At surgery, 40% of patients were ongoing a medical treatment with 5-ASA and/or antibiotics, 40% with steroids and/or immunosoppressors, 15% only with 5-ASA and 5% no ongoing treatment. The horseshoe fistulas were managed with a fistulotomy and seton insertion. One patient with ano-vaginal fistula required proctectomy and the other one total proctocolectomy. Patients treated by diverting colonostomy (3) had fistula recurrence after its closure in 100%. 20% of patients required total proctocolectomy and ileostomy for extensive intestinal disease. Of the 27 patients undergoing seton insertion or fistulotomy none had faecal incontinence due to the operation and 38% had a 1 year recurrence.Perianal CD is a heterogeneous entity, therefore its management is still controversial. Moreover, a high percentage of patients (18% in our series) requires a major surgery due to the extension and seriousness of rectal involvement. In our survey only 12 patients (39%), with trans-sphincteric fistula, could have been theoretically treated with anti-TNF. We wonder if the cost-and-benefit of this medical treatment justifies its application on patients that could undergo a surgical treatment with good long-term results.