Organ xenotransplantation acceptance in veterinary students: A multicentric opinion study in Spain.

BACKGROUND: The shortage of available transplant organs has made it necessary to search for alternatives, one of which is xenotransplantation. However, the use of animal organs could face rejection from society and the personnel involved in its implementation. OBJECTIVES: (a) to analyze the attitudes of Veterinary Degree students in six Spanish Universities towards xenotransplantation; and (b) to determine the factors that affect its acceptance. METHODS: Of the 2815 students surveyed in the degree program, 2683 valid surveys were obtained. Attitudes towards organ xenotransplantation were evaluated using a validated questionnaire of organ donation. RESULTS: If xenotransplantation was confirmed as a clinical reality, 93% (n = 2493) of those surveyed would accept a xenotransplanted organ, whilst 7% would not. If the results of xenotransplantation were worse than those obtained with human donors and it entailed more risk, 12% (n = 318) would be in favor. 56% (n = 1497) of the students would accept a xenotransplantation provisionally pending the arrival of a human organ. Attitudes towards xenotransplantation were affected by the academic year in which a student was studying, with more favorable attitudes among students in the last year (88% in first year vs. 95% in fifth year; p < .001). More favorable attitudes are also observed depending on the attitude they have towards organ transplantation, with those students being more in favor of donating their organs when they die (94% vs. 88%; p < .001). CONCLUSION: Veterinary students would have a very favorable attitude toward xenotransplantation if these animal organs functioned as well as human organs. Therefore, these students could play an important role in the future promotion of this technique.

Myocardial injury after major non-cardiac surgery evaluated with advanced cardiac imaging: a pilot study.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a frequent complication caused by cardiac and non-cardiac pathophysiological mechanisms, but often it is subclinical. MINS is associated with increased morbidity and mortality, justifying the need to its diagnose and the investigation of their causes for its potential prevention. METHODS: Prospective, observational, pilot study, aiming to detect MINS, its relationship with silent coronary artery disease and its effect on future adverse outcomes in patients undergoing major non-cardiac surgery and without postoperative signs or symptoms of myocardial ischemia. MINS was defined by a high-sensitive cardiac troponin T (hs-cTnT) concentration > 14 ng/L at 48-72 h after surgery and exceeding by 50% the preoperative value; controls were the operated patients without MINS. Within 1-month after discharge, cardiac computed tomography angiography (CCTA) and magnetic resonance imaging (MRI) studies were performed in MINS and control subjects. Significant coronary artery disease (CAD) was defined by a CAD-RADS category ≥ 3. The primary outcomes were prevalence of CAD among MINS and controls and incidence of major cardiovascular events (MACE) at 1-year after surgery. Secondary outcomes were the incidence of individual MACE components and mortality. RESULTS: We included 52 MINS and 12 controls. The small number of included patients could be attributed to the study design complexity and the dates of later follow-ups (amid COVID-19 waves). Significant CAD by CCTA was equally found in 20 MINS and controls (30% vs 33%, respectively). Ischemic patterns (n = 5) and ischemic segments (n = 2) depicted by cardiac MRI were only observed in patients with MINS. One-year MACE were also only observed in MINS patients (15.4%). CONCLUSION: This study with advanced imaging methods found a similar CAD frequency in MINS and control patients, but that cardiac ischemic findings by MRI and worse prognosis were only observed in MINS patients. Our results, obtained in a pilot study, suggest the need of further, extended studies that screened systematically MINS and evaluated its relationship with cardiac ischemia and poor outcomes. Trial registration Clinicaltrials.gov identifier: NCT03438448 (19/02/2018).

Is occlusion of the main pancreatic duct by thermal ablation really safe? A surgical innovation assessed according to IDEAL recommendations.

INTRODUCTION: Pre-clinical studies suggest that thermal ablation of the main pancreatic duct (TAMPD) is more recommendable than glue for reducing postoperative pancreatic fistula (POPF). Our aims were (1) to analyze the changes in the pancreas of patients after TAMPD and (2) to correlate the clinical findings with those obtained from a study on an animal model. MATERIALS AND METHODS: A retrospective early feasibility study of a marketed device for a novel clinical application was carried out on a small number of subjects (n = 8) in whom TAMPD was conducted to manage the pancreatic stump after a pancreatectoduodenectomy (PD). Morphological changes in the remaining pancreas were assessed by computed tomography for 365 days after TAMPD. RESULTS: All the patients showed either Grade A or B POPF, which generally resolved within the first 30 days. The duct's maximum diameter significantly increased after TAMPD from 1.5 ± 0.8 mm to 8.6 ± 2.9 mm after 7 days (p = .025) and was then reduced to 2.6 ± 0.8 mm after 365 days PO (p < .0001). The animal model suggests that TAMPD induces dilation of the duct lumen by enzymatic digestion of ablated tissue after a few days and complete exocrine atrophy after a few weeks. CONCLUSIONS: TAMPD leads to long-term exocrine pancreatic atrophy by completely occluding the duct. However, the ductal dilatation that occurred soon after TAMPD could even favor POPF, which suggests that TAMPD should be conducted several weeks before PD, ideally by digestive endoscopy.

Comparison of two radiofrequency-based hemostatic devices: saline-linked bipolar vs. cooled-electrode monopolar.

PURPOSE: To characterize the coagulation zones created by two radiofrequency (RF)-based hemostatic devices: one comprised an internally cooled monopolar electrode and the other comprised externally irrigated bipolar electrodes (saline-linked). MATERIALS AND METHODS: RF-induced coagulation zones were created on ex vivo and in vivo porcine models. Computer modeling was used to determine the RF power distribution in the saline-linked device. RESULTS: Both external (irrigation) and internal cooling effectively prevented tissue sticking. Under ex vivo conditions in 'painting' application mode, coagulation depth increased with the applied power: 2.8 - 5.6 mm with the 3-mm monopolar electrode, 1.6 - 6.0 mm with the 5-mm monopolar electrode and 0.6 - 3.2 mm with the saline-linked bipolar electrodes. Under in vivo conditions and using spot applications, the 3-mm monopolar electrode created coagulation zones of similar depth to the saline-linked bipolar electrodes (around 3 mm), while the 5-mm monopolar electrode created deeper coagulations (4.5 - 6 mm) with less incidence of popping. The presence of saline around the saline-linked bipolar electrodes meant that a significant percentage of RF power (50 - 80%) was dissipated by heating in the saline layer. Coagulation zones were histologically similar for all the tested devices. CONCLUSIONS: Both external (irrigation) and internal cooling in hemostatic RF devices effectively prevent tissue sticking and create similar coagulation zones from a histological point of view. Overall, saline-linked bipolar electrodes tend to create shallower coagulations than those created with an internally cooled monopolar electrode.

Urinary Proteomic Signature in Acute Decompensated Heart Failure: Advances into Molecular Pathophysiology.

Acute decompensated heart failure (ADHF) is a life-threatening clinical syndrome involving multi-organ function deterioration. ADHF results from multifaceted, dysregulated pathways that remain poorly understood. Better characterization of proteins associated with heart failure decompensation is needed to gain understanding of the disease pathophysiology and support a more accurate disease phenotyping. In this study, we used an untargeted mass spectrometry (MS) proteomic approach to identify the differential urine protein signature in ADHF patients and examine its pathophysiological link to disease evolution. Urine samples were collected at hospital admission and compared with a group of healthy subjects by two-dimensional electrophoresis coupled to MALDI-TOF/TOF mass spectrometry. A differential pattern of 26 proteins (>1.5-fold change, p < 0.005), mostly of hepatic origin, was identified. The top four biological pathways (p < 0.0001; in silico analysis) were associated to the differential ADHF proteome including retinol metabolism and transport, immune response/inflammation, extracellular matrix organization, and platelet degranulation. Transthyretin (TTR) was the protein most widely represented among them. Quantitative analysis by ELISA of TTR and its binding protein, retinol-binding protein 4 (RBP4), validated the proteomic results. ROC analysis evidenced that combining RBP4 and TTR urine levels highly discriminated ADHF patients with renal dysfunction (AUC: 0.826, p < 0.001) and significantly predicted poor disease evolution over 18-month follow-up. In conclusion, the MS proteomic approach enabled identification of a specific urine protein signature in ADHF at hospitalization, highlighting changes in hepatic proteins such as TTR and RBP4.

Anatomic, computed tomographic, and ultrasonographic assessment of the lymph nodes in presumed healthy adult cats: The head, neck, thorax, and forelimb.

Assessment of the lymph nodes is key in staging cancer patients. Descriptions of normal features of the feline lymph nodes using computed tomography (CT) and ultrasound (US) are limited. A prospective anatomic and comparative imaging study was performed. The frequency of identification and the size of the lymph nodes during gross pathology from 6 feline cadavers were compared to the images of lymph nodes from 30 presumed healthy adult cats obtained by CT and US. Measurements (length, width, and height) were compared among techniques. The CT and US features of the identified lymph nodes were also recorded. The frequency of identification of the lymph centers varied among techniques and individually. The mandibular lymph nodes were identified in 100% of the cadavers and in 100% of the healthy cats using CT and US. The medial retropharyngeal lymph nodes were identified in 100% of the cats using CT and US. The deep cervical lymph nodes were not visualized in the cadavers. The cranial mediastinal and tracheobronchial lymph nodes were not visualized using US. Lymph nodes showed a higher length on CT and higher width on US. The height was the most statistically significant variable measurement among techniques. On CT, lymph nodes were most frequently isoattenuating or slightly hypoattenuating to surrounding musculature, with homogeneous contrast enhancement. On US, most lymph nodes were isoechoic or hypoechoic to surrounding fat tissue. The lymph nodes were most frequently elongated or rounded.

Valvular heart disease and calcification in CKD: more common than appreciated.

Ischaemic heart disease, sudden cardiac death and arrhythmias, heart failure, stroke and peripheral arterial disease make up >50% of the causes of death in advanced chronic kidney disease (CKD). Calcification of the vascular tree and heart valves is partially related to these complications and has received growing attention in the literature. However, the main focus of research has been on the pathophysiology and consequences of vascular calcification, with less attention being paid to valvular calcification (VC) and its impact on the survival of CKD patients. Although VC has long been seen as an age-related degenerative disorder with minimal functional impact, several studies proved that it carries an increased risk of death and clinical consequences different from those of vascular calcification. In dialysis patients, the annual incidence of aortic valve calcification is nearly 3.3% and the reported prevalence of aortic and mitral VC varies between 25% and 59%. Moreover, calcification of both valves occurs 10-20 years earlier in CKD patients compared with the general population. Therefore, the purpose of this review is to summarize the current knowledge on the pathophysiology and relevance of VC in CKD patients, and to highlight specific clinical consequences and potential therapeutic implications.

The use of sodium-glucose co-transporter 2 inhibitors in the inpatient setting: Is the risk worth taking?

WHAT IS KNOWN AND OBJECTIVE: In the outpatient setting, sodium-glucose co-transporter 2 inhibitors (SGLT2i) are recognized as effective agents to optimize glycaemia and also developing robust evidence for cardiovascular (CV) and renal protection in people with type 2 diabetes, particularly those at higher risk. However, data on the safety and efficacy of these drugs in hospitalized patients remain limited. The purpose of this review is to discuss the balance between risks and benefits of SGLT2i use in the inpatient setting. METHODS: PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the mechanisms of action and the safety profile of SGLT2i in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. RESULTS AND DISCUSSION: The rationale behind the use of these agents in the inpatient setting is based on the low risk of hypoglycaemia, the practical dosing scheme and the potential to decrease subsequent heart failure admission rates. In addition, data from animal studies indicate the ability of SGLT2i to ameliorate oxidative stress, suppress sympathetic activity, enhance autophagy and promote cardiac remodelling, when administered in the acute phase of CV episodes. On the other hand, these drugs have been linked to specific adverse events related to their mechanism of action, including an increased risk of euglycaemic diabetic ketoacidosis and volume depletion, which raises concerns over their usefulness in inpatients, particularly individuals with multimorbidities. WHAT IS NEW AND CONCLUSION: Potential benefits deriving from the use of SGLT2i in the inpatient setting cannot mitigate possible risks, at least until robust evidence on their efficacy in hospitalized individuals become available. The concept of administering these agents in the acute phase of CV episodes, in people with or without diabetes, requires further evaluation in appropriately designed clinical studies.

Development of a catheter-based technique for endoluminal radiofrequency sealing of pancreatic duct.

Introduction: Endoluminal sealing of the pancreatic duct by glue or sutures facilitates the management of the pancreatic stump. Our objective was to develop a catheter-based alternative for endoluminal radiofrequency (RF) sealing of the pancreatic duct. Materials and methods: We devised a novel RF ablation technique based on impedance-guided catheter pullback. First, bench tests were performed on ex vivo models to tune up the technique before the in vivo study, after which endoluminal RF sealing of a ∼10 cm non-transected pancreatic duct was conducted on porcine models using a 3 Fr catheter. After 30 days, sealing effectiveness was assessed by a permeability test and a histological analysis. Results: The RF technique was feasible in all cases and delivered ∼5 W of power on an initial impedance of 308 ± 60 Ω. Electrical impedance evolution was similar in all cases and provided guidance for modulating the pullback speed to avoid tissue sticking and achieve a continuous lesion. During the follow-up the animals rate of weight gain was significantly reduced (p < 0.05). Apart from signs of exocrine atrophy, no other postoperative complications were found. At necropsy, the permeability test failed and the catheter could not be reintroduced endoluminally, confirming that sealing had been successful. The histological analysis revealed a homogeneous exocrine atrophy along the ablated segment in all the animals. Conclusions: Catheter-based RF ablation could be used effectively and safely for endoluminal sealing of the pancreatic duct. The findings suggest that a fully continuous lesion may not be required to obtain complete exocrine atrophy.

Neuromuscular block monitoring after the administration of 1 mg/kg intravenous cis-atracurium in the anaesthetized pig.

Neuromuscular blocking agents should be included as part of a balanced anaesthetic protocol to improve anaesthetic management, although doses are not always established for each species. Cis-atracurium is a benzylisoquinolinium neuromuscular blocking agent with an intermediate duration of action devoid of significant adverse effects previously used in pigs with a wide dosage range. Cis-atracurium was administered at 1 mg/kg bolus to sixteen pigs to establish its time profile and effects. The pigs were premedicated intramuscularly with 4 mg/kg azaperone, 8 mg/kg ketamine and 0.2 mg/kg morphine IM and maintained with isoflurane in oxygen. After cis-atracurium administration, neuromuscular monitoring via acceleromyography was started until the recovery of the 90% of the train of four ratio. Complete decrease in the train of four ratio was accomplished in eleven pigs. Onset of action was 70 s, with a recovery of the fourth twitch at 26 min and a recovery of a train of four ratio greater than 90% in 60 min. In conclusion, 1 mg/kg intravenous cis-atracurium in the pig allowed for a rapid onset of action and a complete recovery after 60 min although high variability in the time profile is seen.

Effect of age on cis-atracurium besylate pharmacokinetics following a single 1 mg kg-1 intravenous bolus in young pigs.

OBJECTIVE: To determine the cis-atracurium pharmacokinetic data and laudanosine production of a single 1 mg kg-1 cis-atracurium dose in the pig and to compare the pharmacokinetics between two groups of different ages. STUDY DESIGN: Prospective experimental study. ANIMALS: Sixteen female pigs in two groups. Group A included eight animals aged 2.0-2.5 months and weighed 26.6 ± 3.6 kg. Group B included eight animals aged 4.0-5.0 months and weighed 57.4 ± 8.3 kg. METHODS: The pigs were anaesthetized and monitored throughout the procedure. Arterial blood samples collected at 0, 0.5, 1, 2, 5, 10, 20, 30, 45, 60, 90, 120 and 180 minutes after cis-atracurium injection were cooled and centrifuged. Plasma was acidified and stored at -20 °C for subsequent cis-atracurium and laudanosine analyses. RESULTS: Anaesthetic parameters were within normal ranges throughout the procedure. Plasma cis-atracurium and laudanosine concentrations were measured for the 16 pigs. Elimination rate constant, elimination half-life, area under the curve, mean residence time, distribution volume and total clearance were calculated for each pig. Statistical differences (p < 0.05) in the elimination rate constant, elimination half-life, mean residence time and distribution volume values were observed between the two groups. Elimination half-life, mean residence time and distribution volume values were higher and elimination rate constant lower in younger pigs than in older pigs. No plasma laudanosine concentrations were detected in any pig. CONCLUSION AND CLINICAL RELEVANCE: Longer duration of plasma cis-atracurium concentrations were observed in younger pigs. Distribution volume was also higher in younger pigs. Conversely, total clearance and area under the curve were similar between the two age groups. No laudanosine production was detected, suggesting a different cis-atracurium metabolism in the pig compared with other species.

Validity and reliability of Doppler ultrasonography and direct arterial blood pressure measurements in anaesthetized dogs weighing less than 5 kg.

OBJECTIVE: To assess the validity and reliability of Doppler ultrasonography (DOP) as compared with invasive arterial blood pressure measurements in anaesthetized dogs weighing less than 5 kg. STUDY DESIGN: Controlled, prospective, clinical study. ANIMALS: A total of 41 privately owned dogs weighing less than 5 kg. METHODS: The dogs were anaesthetized, and an intra-arterial catheter was placed aseptically in the dorsal pedal artery of the pelvic limb to perform invasive blood pressure (IBP) measurement. The contralateral metatarsal surface of the foot was clipped in order to perform DOP. Both techniques were used to record blood pressure measurements every 5 minutes during surgical procedures. The blood pressure measurements were categorized into two groups: hypotensive [mean arterial pressure (MAP) < 60 mmHg] and normotensive (MAP between 60 and 120 mmHg). A linear mixed model was used to compare the DOP and IBP values. The results were evaluated according to the requirements of the American College of Veterinary Internal Medicine (ACVIM) guidelines for the validation of devices. RESULTS: DOP provided higher values compared to the systolic arterial blood pressure (SAP) and MAP of IBP measurements. The closest agreement between the two techniques was found for SAP; the bias was 8.8, and limits of agreement (LOA) were -32.9 and 50.4. Similar results were observed when the IBP technique was categorized. The closest agreement was for SAP in animals categorized as normotensive; the bias was 8.2, and LOAs were -32.8 and 49.2. The level of agreement between DOP and IBP did not meet the ACVIM recommendations. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest there is poor agreement between DOP and IBP measurements in anaesthetized dogs weighing less than 5 kg. Hence, the use of DOP in these animals could be misleading.

Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB.

Lack of relationship between plasma levels of escitalopram and QTc-interval length.

Despite safety concerns raised by the European Medicines Agency (EMA), evidence supporting QT-lengthening effects of escitalopram is far to be conclusive. We aimed to evaluate the relationship between escitalopram plasma levels (Escit-PL) and corrected QT-interval length (QTc-length) in 91 outpatients recruited from a hospital setting. Fifteen patients had an abnormally prolonged QTc-interval, and 3 had QTc-intervals ≥500 ms. No correlation between Escit-PL and QTc-length was found (r = 0.08; p = 0.45). Linear/logistic regression analyses were also conducted taking into account potential confounders such as age, gender, personal history of heart disease, medication load and concomitant use of antipsychotic/tricyclic antidepressants. Escit-PL did not predict either QTc-length or abnormally prolonged QTc-interval. Only antipsychotics/tricyclics use (adjusted ß = 0.26, SE = 9.1; p = 0.01) was an independent predictor of QTc-length (R 2 = 0.096, F = 4.68, df = 2,88; p = 0.01). Only antipsychotics/tricyclics use (OR 3.56 [95% CI 1.01-12.52]; p < 0.05) and medication load (OR 1.32 [95% CI 1.06-1.64]; p < 0.01) were significantly associated with an increased risk of abnormally prolonged QTc-interval (Omnibus test χ 2 = 9.5, df = 2; p < 0.01). Our study did not find a significant relationship between Escit-PL and QTc-length even when recognized modulating factors of the QT-interval were controlled for. Concomitant use of other potentially arrhythmogenic agents may help to explain the apparent link between escitalopram and QT prolongation previously suggested. The advisability of maintaining the EMA warning is once again called into question.

Impact of monopolar radiofrequency coagulation on intraoperative blood loss during liver resection: a prospective randomised controlled trial.

PURPOSE: To evaluate the impact of using monopolar thermal coagulation based on radiofrequency (RF) currents on intraoperative blood loss during liver resection. MATERIALS AND METHODS: A prospective randomised controlled trial was planned. Patients undergoing hepatectomy were randomised into two groups. In the control group (n = 10), hemostasis was obtained with a combination of stitches, vessel-sealing bipolar RF systems, sutures or clips. In the monopolar radiofrequency coagulation (MRFC) group (n = 18), hemostasis was mainly obtained using an internally cooled monopolar RF electrode. RESULTS: No differences in demographic or clinical characteristics were found between groups. Mean blood loss during liver resection in the control group was more than twice that of the MRFC group (556 ± 471 ml vs. 225 ± 313 ml, p = .02). The adjusted mean bleeding/transection area was also significantly higher in the control group (7.0 ± 3.3 ml/cm2 vs. 2.8 ± 4.0 ml/cm2, p = .006). No significant differences were observed in the rate of complications between the groups. CONCLUSIONS: The findings suggest that the monopolar electrocoagulation created with an internally cooled RF electrode considerably reduces intraoperative blood loss during liver resection.

Focused Transhepatic Electroporation Mediated by Hypersaline Infusion through the Portal Vein in Rat Model. Preliminary Results on Differential Conductivity.

BACKGROUND: Spread hepatic tumours are not suitable for treatment either by surgery or conventional ablation methods. The aim of this study was to evaluate feasibility and safety of selectively increasing the healthy hepatic conductivity by the hypersaline infusion (HI) through the portal vein. We hypothesize this will allow simultaneous safe treatment of all nodules by irreversible electroporation (IRE) when applied in a transhepatic fashion. MATERIAL AND METHODS: Sprague Dawley (Group A, n = 10) and Athymic rats with implanted hepatic tumour (Group B, n = 8) were employed. HI was performed (NaCl 20%, 3.8 mL/Kg) by trans-splenic puncture. Deionized serum (40 mL/Kg) and furosemide (2 mL/Kg) were simultaneously infused through the jugular vein to compensate hypernatremia. Changes in conductivity were monitored in the hepatic and tumour tissue. The period in which hepatic conductivity was higher than tumour conductivity was defined as the therapeutic window (TW). Animals were monitored during 1-month follow-up. The animals were sacrificed and selective samples were used for histological analysis. RESULTS: The overall survival rate was 82.4% after the HI protocol. The mean maximum hepatic conductivity after HI was 2.7 and 3.5 times higher than the baseline value, in group A and B, respectively. The mean maximum hepatic conductivity after HI was 1.4 times higher than tumour tissue in group B creating a TW to implement selective IRE. CONCLUSIONS: HI through the portal vein is safe when the hypersaline overload is compensated with deionized serum and it may provide a TW for focused IRE treatment on tumour nodules.

Long-term evolution of acinar-to-ductal metaplasia and ß-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model.

BACKGROUND: Pancreatic duct ligation (PDL) has been used as a model of chronic pancreatitis and as a model to increase ß-cell mass. However, studies in mice have demonstrated acinar regeneration after PDL, questioning the long-term validity of the model. We aim to elucidate whether RF-assisted transection (RFAT) of the main pancreatic duct is a reliable PDL model, both in short (ST, 1-month) and long-term (LT, 6-months) follow-ups. METHODS: Eleven pigs were subjected to RFAT. Biochemical (serum/peripancreatic amylase and glucose) and histological changes (including a semiautomatic morphometric study of over 1000 images/pancreas and IHC analysis) were evaluated after ST or LT follow-up and also in fresh pancreas specimens that were used as controls for 1 (n = 4) and 6 months (n = 6). RESULTS: The distal pancreas in the ST was characterized by areas of acinar-to-ductal metaplasia (56%) which were significantly reduced at LT (21%) by fibrotic replacement and adipose tissue. The endocrine mass showed a normal increase. CONCLUSION: RFAT in the pig seems to be an appropriate PDL model without restoration of pancreatic drainage or reduction of endocrine mass.

Selected CD133⁺ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial.

RATIONALE: Refractory angina constitutes a clinical problem. OBJECTIVE: The aim of this study was to assess the safety and the feasibility of transendocardial injection of CD133(+) cells to foster angiogenesis in patients with refractory angina. METHODS AND RESULTS: In this randomized, double-blinded, multicenter controlled trial, eligible patients were treated with granulocyte colony-stimulating factor, underwent an apheresis and electromechanical mapping, and were randomized to receive treatment with CD133(+) cells or no treatment. The primary end point was the safety of transendocardial injection of CD133(+) cells, as measured by the occurrence of major adverse cardiac and cerebrovascular event at 6 months. Secondary end points analyzed the efficacy. Twenty-eight patients were included (n=19 treatment; n=9 control). At 6 months, 1 patient in each group had ventricular fibrillation and 1 patient in each group died. One patient (treatment group) had a cardiac tamponade during mapping. There were no significant differences between groups with respect to efficacy parameters; however, the comparison within groups showed a significant improvement in the number of angina episodes per month (median absolute difference, -8.5 [95% confidence interval, -15.0 to -4.0]) and in angina functional class in the treatment arm but not in the control group. At 6 months, only 1 simple-photon emission computed tomography (SPECT) parameter: summed score improved significantly in the treatment group at rest and at stress (median absolute difference, -1.0 [95% confidence interval, -1.9 to -0.1]) but not in the control arm. CONCLUSIONS: Our findings support feasibility and safety of transendocardial injection of CD133(+) cells in patients with refractory angina. The promising clinical results and favorable data observed in SPECT summed score may set up the basis to test the efficacy of cell therapy in a larger randomized trial.