Curcumin induced oxidative stress attenuation by N-acetylcysteine co-treatment: a fibroblast and epithelial cell in-vitro study in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology with only two federally approved drug options. Given the complex molecular pathogenesis of IPF involving multiple cell types and multiple pathways, we explore the effects of a potential antifibrotic and antioxidant drug combination. Curcumin is a polyphenolic compound derived from turmeric with significant biological activity including a potential antifibrotic capacity. N-acetylcysteine (NAC) is a precursor to the antioxidant glutathione. To advance our understanding of these molecules, and to identify a clinical application, we present a small number of focused experiments that interrogates the effect of curcumin and NAC on pathways relevant to IPF in both fibroblasts and epithelial cells. METHODS: Primary epithelial cell and fibroblasts isolated from patients with IPF were challenged with a combination treatment of NAC and curcumin. Evaluation of the antifibrotic potential and effect on oxidative stress was performed through QPCR gene expression analysis and functional assays including scratch tests, viability assays, and measurement of induced reactive oxygen species. RESULTS: We demonstrate that curcumin alone does have antifibrotic potential, but that effect is accompanied by proapoptotic increases in oxidative stress. Coupled with this, we find that NAC alone can reduce oxidative stress, but that epithelial cell viability is decreased through this treatment. However, co-administration of these two molecules decreases oxidative stress and maintains high cell viability in both cell types. In addition, this co-treatment maintains an antifibrotic potential. CONCLUSIONS: These findings suggest a novel application for these molecules in IPF and encourage further exploration of this potential therapeutic approach.

T1 colon cancer in the era of screening: risk factors and treatment.

BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.

Malnutrition in Healthy Individuals Results in Increased Mixed Cytokine Profiles, Altered Neutrophil Subsets and Function.

Malnutrition is commonly associated with increased infectious disease susceptibility and severity. Whereas malnutrition might enhance the incidence of disease as well as its severity, active infection can in turn exacerbate malnutrition. Therefore, in a malnourished individual suffering from a severe infection, it is not possible to determine the contribution of the pre-existing malnutrition and/or the infection itself to increased disease severity. In the current study we focussed on two groups of malnourished, but otherwise healthy individuals: moderately malnourished (BMI: 18.4-16.5) and severely malnourished (BMI <16.5) and compared several immune parameters with those of individuals with a normal BMI (≥18.5). Our results show a similar haematological profile in all three groups, as well as a similar ratio of CD4+ and CD8+ T cells. We found significant correlations between low BMI and increased levels of T helper (Th) 1 (Interferon (IFN)-γ, (interleukin (IL)-2, IL-12), Th2 (IL-4, IL-5, IL-13), as well as IL-10, IL-33 and tumor necrosis factor-α, but not IL-8 or C reactive protein. The activities of arginase, an enzyme associated with immunosuppression, were similar in plasma, peripheral blood mononuclear cells (PBMC) and neutrophils from all groups and no differences in the expression levels of CD3ζ, a marker of T cell activation, were observed in CD4+ and CD8+T cells. Furthermore, whereas the capacity of neutrophils from the malnourished groups to phagocytose particles was not impaired, their capacity to produce reactive oxygen species was impaired. Finally we evaluated the frequency of a subpopulation of low-density neutrophils and show that they are significantly increased in the malnourished individuals. These differences were more pronounced in the severely malnourished group. In summary, our results show that even in the absence of apparent infections, healthy malnourished individuals display dysfunctional immune responses that might contribute to increased susceptibility and severity to infectious diseases.

Enhanced recovery after surgery (ERAS) pathway vs traditional care in laparoscopic rectal resection: a single-center experience.

BACKGROUND: The aim of this study was to compare the outcome of an enhanced recovery after surgery (ERAS) pathway with traditional perioperative care in laparoscopic rectal resection. METHODS: A retrospective analysis of prospectively collected data was conducted. Single-center consecutive patients who underwent laparoscopic rectal surgery after an ERAS program were compared with patients who received traditional care over an 8-year period. Primary and total length of stay, and readmission, morbidity and mortality rates were analyzed. For ERAS group, the actual adherence to protocol was also evaluated. RESULTS: Two hundred and ninety-seven patients, 162 in the ERAS group and 135 in conventional care, were studied. Median primary and total length of stay were significantly shorter in the ERAS group (9 vs 12 days; p = 0.0001; 10 vs 12 days; p = 0.01; respectively). The ERAS group experienced a faster recovery of bowel function than the traditional care group (p = 0.0001). A similar morbidity rate was observed in the two groups (32.3 % in ERAS vs 36.1 % in traditional care p = 0.41). Readmission rates were 4.9 % in the ERAS versus 1.5 % in the traditional care group (p = 0.19). There was no mortality in either group. Overall mean compliance with the ERAS protocol was 85.7 % (range 54.4-100 %). CONCLUSIONS: The introduction of the ERAS protocol in laparoscopic rectal resection led to a reduction in primary and total length of hospital stay without an increase in morbidity or readmission rates when compared to traditional care.

Hemorrhoid laser procedure for second- and third-degree hemorrhoids: results from a multicenter prospective study.

BACKGROUND: The aim of our study was to assess the outcome of hemorrhoidal dearterialization, achieved by a dedicated laser energy device. METHODS: From November 2012 to December 2014, 51 patients with second- or third-degree hemorrhoids were studied. The primary end point was a reduction in the bleeding rate; secondary end points were: postoperative complications, reduction in pain and prolapse, resolution of symptoms, and degree of patient's perception of improvement. The procedure was carried out as 1-day surgery. A diode laser device was employed to seal the terminal branches of the hemorrhoidal arteries, detected by a Doppler-equipped proctoscope. Follow-up was scheduled at 1 and 4 weeks, 3, 12, and 24 months. The rate and degree of symptoms was assessed with a four-point verbal rating scale. The rate of subjective symptomatic improvement was also evaluated with the Patient Global Improvement (PGI) Scale. RESULTS: Mean bleeding and pain scores at baseline were 2 and 0.57. All the patients were discharged on the day of surgery. Postoperative complications were bleeding (n = 4) and external hemorrhoidal thrombosis (n = 4). Mean bleeding and pain scores at 3, 12, and 24 months were significatively reduced. After 24 months, complete resolution of bleeding was observed in 28/29 patients (96.7 %), resolution of pain in all patients, and resolution of the mucosal prolapse in 15/18 patients (76.9 %). At 12-month follow-up, 86.3 % of patients reported improvement with the PGI Scale. CONCLUSIONS: The hemorrhoid laser procedure was effective in improving bleeding and pain symptoms in patients with grade II and III hemorrhoids.

In vitro hemodynamics and valve imaging in passive beating hearts.

Due to their high complexity, surgical approaches to valve repair may benefit from the use of in vitro simulators both for training and for the investigation of those measures which can lead to better clinical results. In vitro tests are intrinsically more effective when all the anatomical substructures of the valvular complexes are preserved. In this work, a mock apparatus able to house an entire explanted porcine heart and subject it to pulsatile fluid-dynamic conditions was developed, in order to enable the hemodynamic analysis of simulated surgical procedures and the imaging of the valvular structures. The mock loop's hydrodynamic design was based on an ad-hoc defined lumped-parameter model. The left ventricle of an entire swine heart was dynamically pressurized by an external computer-controlled pulse duplicator. The ascending aorta was connected to a hydraulic circuit which simulated the input impedance of the systemic circulation; a reservoir passively filled the left atrium. Accesses for endoscopic imaging were located in the apex of the left ventricle and in the aortic root. The experimental pressure and flow tracings were comparable with the typical in vivo curves; a mean flow of 3.5±0.1l pm and a mean arterial pressure of 101±2 mmHg was obtained. High-quality echographic and endoscopic video recordings demonstrated the system's excellent potential in the observation of the cardiac structures dynamics. The proposed mock loop represents a suitable in vitro system for the testing of minimally-invasive cardiovascular devices and surgical procedures for heart valve repair.

Protection of intestinal anastomosis with biological glues: an experimental randomized controlled trial.

BACKGROUND: The aim of the study was to compare the degree of healing and air tightness of hand-sewn colonic anastomoses provided by different biological glues. METHODS: Thirty colonic anastomoses were fashioned in ten rabbits, at 5, 10, 15 cm from the ileocecal valve, with 4/0 PDS running sutures. Each suture was randomized to treatment with fibrin sealant (Tissucol®), a synthetic glue (Coseal®), or nothing (control). After 15 days, the rabbits were killed and the anastomoses examined for their integrity and resistance to bursting. The van der Hamm scale was used to evaluate postoperative adhesions. A blind histological evaluation of the newly formed tissue was made (Ehrlich-Hunt scale). RESULTS: Two rabbits developed an intraabdominal abscess, one in the control anastomosis group without glue. Postoperative adhesions were present in all animals. Median anastomosis bursting pressures were 0.9 atm in all three groups: Tissucol, Coseal, and control. Pressure values were 0.9, 1.0, and 0.9 atm in the three different proximodistal sites, respectively. A trend toward an increased resistance was observed in the glued anastomosis, although this was not significant. Lymphocyte infiltration, fibroblast activity, blood vessel density, and collagen deposition were lower in controls. Anastomoses treated with Tissucol had the highest lymphocyte infiltration level. The Coseal group developed the highest rates of fibroblast activity, collagen deposition, and blood vessel neogenesis. CONCLUSION: The use of biological glues did not result in a statistically significantly increased bursting resistance. Histological evaluation demonstrated more intense tissue neoformation in the glue groups, particularly in the Coseal group. The role of biological glues in decreasing the leakage rate of intestinal anastomoses is uncertain, and larger trials using different protective agents are warranted.

Fecal incontinence: up to date on pathophysiology and treatment.

This study analyzes the most recent insight into the pathophysiology of fecal incontinence considering each of the factors contributing to the mechanism of fecal continence both during urgency to defecate and in resting state. In fact different types of incontinence are caused by different damage to one or more of these physiologic factors. The second part of the study focuses on the therapeutic choices of fecal incontinence. The recent introduction of sacral nerve electrostimulation and the progressive broadening of its clinical indications is progressively replacing and challenging other traditional surgical techniques because of their disappointing long-term results and because they are much more invasive. An emerging new treatment based on the injection of anal bulking agents is nowadays even more preferred for the less severe cases of fecal incontinence. An increasing number of materials is now proposed by the industry in order to identify the best biocompatible material to be injected trans-anally. Traditional surgery could be reserved for patients non-responding to these new treatments.

Should pregnancy be considered a risk factor for aortic dissection? Two cases of acute aortic dissection following cesarean section in non-Marfan nor bicuspid aortic valve patients.

Acute aortic dissection in pregnancy is a rare event and rarer still in healthy young women; however, women with a bicuspid aortic valve or the Marfan syndrome are at a higher risk of dissection. The relationship between pregnancy and aortic dissection is still unclear. We describe the cases of two women with no history of cardiovascular disease who developed an acute aortic type A dissection within a few days after term delivery. Surgical repair was performed with ascending aorta replacement and aortic valve sparing. In both cases, the dissection was diagnosed within a few days following cesarean section done neither because of fetal or maternal distress. To date, only one case of type A and two cases of type B aortic dissection following cesarean section have been reported. Compared with spontaneous delivery, scheduled cesarean section, as in our cases, allows for better control of hemodynamic parameters and should protect against aortic dissection. Postoperative screening for inherent connective tissue disorders detected no mutations within the fibrillin and collagen gene chromosome in either patient. Postoperative recovery was uneventful, and the patients were discharged on postoperative days 7 and 8, respectively.

Does the Ventrica magnetic vascular positioner (MVP) for coronary artery bypass grafting significantly alter local fluid dynamics? A numeric study.

OBJECTIVE: Automatic devices have been recently introduced to make the anastomosis procedure quick and efficient when creating a coronary bypass on the beating heart. However, the implantation of these devices could modify the graft configuration, consistently affecting the hemodynamics usually found in the traditional anastomosis. As local fluid dynamics could play a significant role in the onset of vessel wall pathologies, in this article a computational approach was designed to investigate flow patterns in the presence of the Ventrica magnetic vascular positioner (Ventrica MVP) device. METHODS: A model of standard hand-sewn anastomosis and of automated magnetic anastomosis were constructed, and the finite volume method was used to simulate in silico realistic graft hemodynamics. Synthetic analytical descriptors -- i.e., time-averaged wall shear stress (TAWSS), oscillating shear index (OSI) and helical flow index (HFI) -- were calculated and compared for quantitative assessment of the anastomosis geometry hemodynamic performance. RESULTS: In this case study, the same most critical region was identified for the 2 models as the one with the lowest TAWSS and the highest OSI (TAWSS=0.229, OSI=0.255 for the hand-sewn anastomosis; TAWSS=0.297, OSI=0.171 for the Ventrica MVP(R)). However, the shape of the Ventrica MVP does not induce more critical wall shear stresses, oscillating flow and damped helicity in the graft fluid dynamics, as compared with conventional anastomosis. CONCLUSIONS: We found that the use of the Ventrica MVP for the case study under investigation was not associated with more critical fluid dynamics than with conventional hand-sewn anastomosis. Thereby, the device could facilitate beating heart and minimally invasive coronary artery bypass grafting without increasing local hemodynamic-related risks of failure.

Myocardial revascularization with multiple arterial grafts: comparison between the radial artery and the right internal thoracic artery.

BACKGROUND: Bilateral internal thoracic artery (ITA) harvesting is significantly underused, whereas the radial artery is being used with increasing frequency. We have retrospectively analyzed perioperative and short-term outcomes of patients receiving a radial artery versus those receiving a right ITA as a second arterial graft. METHODS: Between February 1999 and May 2000, 250 patients underwent coronary artery bypass grafting using the radial artery (156 patients) or the right ITA (94 patients) in combination with the left ITA and, when required, the saphenous vein. RESULTS: There was a higher prevalence of risk factors in the radial artery group. More coronary artery bypass graftings (p < 0.001) were performed with the radial artery. Operative mortality was not different (p = not significant). In the right ITA group there was more bleeding (p < 0.001) and a longer hospital stay (p < 0.001). Mean follow-up was 8.1 +/- 3.9 months. The probability of survival was similar (p = not significant). CONCLUSIONS: The radial artery can extend the benefits of multiple arterial grafting to those patients who are usually excluded from bilateral ITA harvesting because of multiple risk factors. Perioperative and short-term results are good.

Early failure associated with the use of Hylamer-M spacers in three primary AMK total knee arthroplasties.

We report 3 cases of early failure associated with AMK total knee arthroplasties with the use of Hylamer-M spacers. In 2 of these cases, massive osteolysis of the posterior condyles was noted; revision with the use of allograft bone to fill in the cavitary defects yielded excellent results. In all cases, large areas of pitting and delamination of the Hylamer spacers were noted. Given these cases and the previous literature on early failure of hip arthroplasties with Hylamer inserts, we recommend caution in using Hylamer for knee arthroplasty surgery.

[Left atrium rupture after non-penetrating injury to the back]. / Rottura di auricola sinistra dopo trauma non penetrante del dorso.

Survival after cardiac rupture associated with blunt thoracic trauma is very uncommon. In these patients successful management demands a high index of suspicion of cardiac injury. A case of a 24-year-old woman who presented unconscious and shocked in the emergency room after motorcycle trauma strictly limited to her back is reported. Rib and sternal fractures were absent; the typical signs of cardiac tamponade were not found. Therefore the suspicion of cardiac chamber rupture was not immediate and the cardiologist was consulted after several diagnostic exams. Transthoracic echocardiography showed a pericardial effusion with clots and initial cardiac tamponade. The patient was transferred to the operating room and a large hemopericardium was disclosed. Two lacerations were noticed: the first pericardial, near the inferior vena cava, and the second one in the posterior wall of the left atrium. It is possible that the associated pericardial tear and pericardial clots could have contributed to survival. After surgical repair, carried out during cardiopulmonary bypass, the recovery was quick and complete. This case report confirms the possibility of heart chamber rupture after blunt chest trauma even in the absence of obvious thoracic lesion and it shows that the presentation could be very insidious without a "classic" clinical picture of cardiac tamponade. In front of an unexplained shock after nonpenetrating thoracic trauma, a rupture of the heart chambers should be suspected and echocardiography is mandatory. In the emergency room environment pericardiocentesis should be performed only with a quickly available cardiac surgery or in the presence of overwhelming hemodynamic failure.

Treatment of anterior mitral leaflet prolapse: chordal suture plication and free-edge remodeling in 34 patients.

In this study are considered the short-middle term results of anterior mitral leaflet prolapse repair obtained by means of a personal operative technique: chordal shortening and free edge remodeling. In our institution since 1993 34 consecutive patients with degenerative myxomatous mitral regurgitation, (mean age 63.3 years, range 25 to 83 years), underwent surgery. Before the operation 22 patients (64.7%) were in NYHA functional class III or IV. Mitral insufficiency, evaluated by echocardiogram, was severe in all patients; a prolapse of only anterior leaflet was present in 10 patients, both leaflets prolapsed in the others. Patients with chordal rupture of anterior mitral leaflet were excluded. Anterior mitral leaflet prolapse repair was performed with two continuous sutures including the free edge as well as the chordae for a variable length (2 mm up to 5 mm) depending on the degree of the elongation. A concomitant posterior leaflet quadrangular resection was performed in 24 patients (70.5%), and the procedure was almost always completed by a posterior suture annuloplasty reinforced by a glutaraldehyde-tanned strip of autologous pericardium. There were no perioperative deaths. The postoperative course was uneventful in all cases, and there were no hospital deaths. Postoperative echocardiographic evaluation showed satisfactory valve function. The mean valvular regurgitation before surgical procedure was 3.67 +/- 0.4, after repair 0.30 +/- 0.5 (p < 0.01). Follow-up was completed in all patients (mean 16.5 months) with no late deaths. One patient required early reoperation for recurrent mitral regurgitation resulting for a recurring anterior leaflet prolapse. We conclude that this technique is a safe, effective and easy procedure for the repair of anterior mitral leaflet prolapse without rupture. Nevertheless, a larger number of patients and a longer follow-up are required to confirm our results.

Myocardial revascularization in patients with ischemic cardiomyopathy: functional observations.

OBJECTIVE: A prospective angiographic study was undertaken to investigate, with an objective analysis, the global and regional wall response to myocardial revascularization. METHODS: Thirty-one patients (30 men and 1 woman, mean age, 61 years) with a left ventricular ejection fraction of less than 0.30 were admitted to our institution between 1992 and 1995 for two- or three-vessel coronary artery disease requiring myocardial revascularization. All patients underwent isolated coronary artery bypass grafting and were studied 3 months later with angiography. Preoperative and postoperative wall motion were analyzed using special software that computed a segmental left ventricular ejection fraction, generating a segmental score. Computerized analysis allowed us to distinguish patients with diffuse hypokinesis and a symmetric contraction pattern from patients with akinesis involving at least two segments and an asymmetric contraction pattern. RESULTS: There were no operative deaths and no patient required intraaortic balloon counterpulsation. One patient had postoperative enzymatic evidence of myocardial infarction. Postoperative angiography showed a graft patency rate of 84%. Global analysis showed a small but significant rise in the left ventricular ejection fraction (0.25 +/- 0.51 to 0.31 +/- 0.70, p < 0.001) and a fall in the left ventricular end-diastolic pressure (23.7 +/- 10 to 16.5 +/- 9 mm Hg, p < 0.01). Mean scores always have been lower after the operation than before it, with the best results obtained for the apex and the worst for the anterobasal segment. The group with a symmetric contraction pattern showed a trend toward a better hemodynamic response than the group with an asymmetric contraction pattern. Regression analysis revealed two important predictors of segmental functional improvement: (1) the absence of an echocardiographic scar, and (2) the presence of a collateral circulation. CONCLUSIONS: Coronary artery bypass grafting produced a small but substantial improvement in patients with ischemic cardiomyopathy. The greater benefit occurred in patients with a symmetric contraction pattern. The absence of an echocardiographic scar and the presence of a collateral circulation predicted segmental functional improvement.

[Antioxidant action of Foy in an experimental model of hypergeneration of oxygen free radicals]. / Azione antiossidante del Foy in un modello sperimentale di ipergenerazione di radicali liberi dell'ossigeno.

BACKGROUND: Several trials have just demonstrated the therapeutic efficacy of gabexate mesylate (Foy). For this drug numerous mechanisms of action have been postulated; protease inhibition, direct or indirect lysosomal membrane stabilization, etc. The aim of this study has been to verify if Foy would express antioxidant properties against free radical overgeneration, responsible for the increase in microvascular permeability which represents one of the most important pathogenetic phenomenon of any condition of shock. A mixture of hypoxanthine-xanthine oxidase has been used to obtain a generation of oxygen free radicals in vivo. METHODS: Experiments were performed on the mesocecum of male Wistar rats; fluorescent labelled bovine albumin has been injected intra-arterially to evaluate the capillary permeability and the mesocecum microcirculation has been observed by fluorescent microscopy. The control group received saline i.v., the second group received topically applied on the mesocecum a mixture of 0.96 mM hypoxanthine and 0.05 UI/ml xanthine oxidase; the third and the fourth groups were pretreated respectively with a topical application and continuous infusion of a Foy 1% solution (50 ml/kg/min). To evaluate capillary permeability and to quantify the degree of extravasation by counting the number of leaky sites, labelled bovine albumin was injected i.a. and mesocecum was observed with fluorescent microscopy for 2 hours. RESULTS AND CONCLUSION: Gabexate mesilate (Foy) exerts its efficacy preventing the increase in capillary permeability provoked by an overgeneration of free radicals; it could express antioxidant properties.

[Antioxidant action of gabexate mesilate (Foy) in an experimental model of endotoxic shock]. / Azione antiossidante del gabesato mesilato (Foy) in un modello sperimentale di shock endotossinico.

BACKGROUND: Circulatory shock, especially endotoxin shock, is characterized by the release of a large number of mediators, among which proteases play a key role. The production of oxygen free radicals into the extracellular space and the increase of capillary permeability is one of the most important consequences of that phenomenon. In order to evaluate the efficacy of gabexate mesilate (Foy) in preventing such increase of microvascular permeability, an experimental model of endotoxin shock was used. MATERIALS AND METHODS: Experiments were performed on the mesocecum of male Wistars rats, fluorescent labeled bovine albumine was injected intrarterially to evaluate the capillary permeability and the mesocecum microcirculation was observed by fluorescent light. The control group received saline i.v.; the II group received a DL 100 of E. coli endotoxin (DIFCO 0111: B4); the III and the IV group received a continuous infusion or topical application of gabexate mesilate respectively, before the administration of endotoxin. To evaluate capillary permeability and to quantify the degree of extravasion by counting the number of leaky sites, fluorescent labelled bovine albumin was injected i.v. and mesocecum was observed with fluorescent microscopy for 2 hours. RESULTS AND CONCLUSIONS: Capillary permeability did not increase in control rats; it largely increased in rats receiving endotoxin i.v. but it did not almost increased in rats receiving gabexate mesilate (Foy) that prevents the increase of capillary permeability that was observed in the group treated with endotoxin alone.