Manipulating the Barrier Function of a Cell Monolayer Using a High-power Miniature Ultrasonic Transducer

Ultrasound (US) and cavitation agents such as microbubbles (MBs) have been demonstrated to decrease the barrier function of endothelial and epithelial layers. However, in vitro experiments that study this effect are often hindered by the inability to deliver buoyant contrast agents in proximity to cell monolayers in order to adequately control the decrease in barrier function whilst insonating a sufficiently large tissue area. We have addressed this by adapting a cell culture system and fabricating a bespoke high-power miniature unfocused US transducer. The setup was used to control the drop in barrier function and to determine how varying the mechanical index (MI) and the duty cycle affected the barrier function. It was found that buffer solution alone and buffer + MBs did not decrease the transepithelial electrical resistance (TEER) of the cell monolayer. Buffer + US decreased the TEER by ~40%, with 10% TEER recovery 9 min after switching US off. Buffer + MBs + US decreased the TEER by 80%, with little or no recovery following treatment. In the presence of MBs, the barrier function was decreased by a duty cycle = [1% - 50%] and by an MI = [0.25 - 0.5], without any recovery following treatment. Detectable amounts of fluorescent dextran were delivered across the Caco-2 monolayer only by a combination of US + MBs. These results suggest that our adapted setup and custom-built miniature transducer permits control of the decrease in barrier function for further therapeutic investigations

Mediastinitis after cardiac surgery

Departamentul Cardiochirurgie SCR, Al XI-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova și cea de-a XXXIII-a Reuniune a Chirurgilor din Moldova „Iacomi-Răzeșu” 27-30 septembrie 2011Scopul lucrării. Mediastenita anterioară după operații pe cord, determină o rată sporită a morbidității, care denotă mărirea costului mediu a cazului tratat a acestui contingent de pacienți. Scopul acestui studiu a fost de a determina cauzele ce condiționează apariția mediastinitei postoperatorie. Metode şi materiale. În perioada anilor 2000 - 2010 au suportat intervenţie chirurgicală pe cord 2634 pacienţi. La 44 (1,67%) de pacienți perioada postoperatorie s-a complicat cu infectarea plăgii. În 22 (50%) cazuri s-a dezvoltat mediastenita anterioară și în 22 (50%) cazuri infectarea plăgii pînă la stern, ulterior s-a dezvoltat mediastinita cu sau fără dehiscența sternului.Grupul de pacienți a fost constituit din 30 (68,1%) bărbați şi 14(31,9%) femei, cu vîrsta medie de 59 de ani. Preoperator 20 (45%) pacienți erau obezi, 6 (13,6%) sufereau de diabet zaharat și 7 (16%) bronhopneumopatie cronică obstructivă. Pentru By-pass aortocoronarian s-a folosit artera toracică internă (ATI) unilateral în 18 (40%) şi bilateral la 1 (2,3%) pacient. Timpul intervenției chirurgicale în mediu a alcătuit 345min. Transfuzii masive postoperator au necesitat 5 (11,3%) pacienți. Diagnosticul de mediastenita a fost stabilit la a 5 - 17 zi postoperator. Restabilirea integrității sternale cu aplicarea procedeului Robicsek s-a efectuat la 14(31,8%) pacienți. A decedat 1 pacient (2,3%) din acest grup, cu mediastinita sero-purulentă la a - 20 zi postoperaror din cauza insuficienței poliorganice. La 4 pacienți s-a dezvoltat osteomielită sternală, care a necesitat tratament de lungă durată (3 - 6 luni). Concluzia: Studiul sugerează că utilizarea ATI uni sau bilaterale, bronhopneumopatie cronica obstructivă, diabetul zaharat, obezitatea, transfuziile masive, timpul îndelungat a operației sunt predictori importanți de mediastinită anterioară.Abstract. Background: Mediastinitis is a serious complication of cardiac surgery. It has a significantsocioeconomic impact and high morbidity. The purpose of this study was to determine perioperative predictors of mediastinitis. Methods and results: From 2634 consecutive pacients, which underwent cardiac surgery in 2000-2010. In forty-four pacients (1.67%) postoperative period was complicated by wound infection. In 22 (50%) cases developed earlier mediastenitis and 22 (50%) cases sternum wound infection subsequently developed mediastinitis with or without dehiscence of the sternum. In this group of pacients 30 were men (68.1%) and 14 women (31.9%) of average age 59 years. Preoperator, 20 (45%) of them had obesity, 6 (13.6%) suffered of diabetes mellitus and 7 (16%) of chronic obstructive pulmonary disease. As a graft for Coronary Artery Bypass (IMA) was used unilaterally 18 (40%) and bilateral 1 (2.3%) pacient. The average time of surgery duration was 345 min. Massive transfusion after surgery was certified on five pacients (11.3%). Diagnosis of Mediastenitis was established at the 5 - 17 days postoperatively. Restoration of sternal integrity with the Robicsek proceeding was performed in 14 (31.8%) pacients.One pacient 1(2.3%) of this group with mediastinitis diet after 20 days postoperative, due to failure Multiple Organ System Dysfunctions. In four pacients developed sternal osteomyelitis, requiring long-term treatment (3-6 months). Conclusion: The present study suggest that uni/bilateral internal mammary artery grafting, chronic obstructive pulmonary disease, obesity, massive transfused units and long surgery duration are important predictors of mediastinitis

Citochinele pro- și antiinflamatoare la pacienți cu hepatitele cronice virale la tratament cu BioR

State Medicine and Pharmaceutics University “Nicolae Testemitanu”, Chisinau, Republic of MoldovaSummary. Introduction: T-cell immunoregulatory cytokines influence the persistenceof hepatitis C and B virus (HCV, HBV) chronic infection and the extent of liver damage. Th1 cytokines positively correlate with hepatic inflammation in HBV and HCV chronic infection. The proinflammatory cytokines are involved inviral clearance and in metabolic and viral hepatic diseases,respectively. The aim of this study is to evaluate the biochemical, haematological parameters and profileof Th1/Th2 cytokines in HCV and HBV hepatitis before and after treatment with BioR. Methods: The study included 42 patients with chronic viral hepatitis. Following the aim the establishment of the viral hepatitis aetiology it was decided to define the markers of the viral hepatitis, the antibodies antiHCV total, antiHCV IgM, HbsAg, antiHBs, antiHBcor total and IgM, as well as to identify the alcohol consumption through use of different questionnaires. Along with the evaluation of the liver status also the abdominal ecography and the hepatic gamma-scintigraphy or scanning of the liver has been performed. The immunoenzymatic assay has been used to study the interleukins 1, 10 and TNF-alpha. Patients included in the study have been administered the injection solution of BioR, 1.0 ml intramuscular, daily, during 10 days. Results: Our study has indicated that BioR causes a number of haematological actions in case of patients with HCV. Thus, patients with HCV show a real amelioration of haemoglobin (p<0.05), and of lymphocyte levels (p<0.05) compared to patients with HBV. In result of the application of a therapy with BioR an evident diminution of cytolysis (ALT, AST) takes place both in patients with HBV (p<0.05) and in the ones with HCV (p<0.05). This indicates the fact that BioR plays the role of a hepatic protector. It has been also proven that BioR reduces gamma GTP in patients with HCV (p0.05), indicating to the occurrence of a disintoxication. This study has shown that a treatment with BioR brings about the stimulation of production of IL 10, TNF alpha in patients with HCV and HBV. We consider this action a key mechanism of this preparate with antiviral effect, and we recommend it for treatment of persons with viral hepatitis. Conclusions: This study indicates that the use of the BioR preparate in chronic viral B and C hepatitis is justified, given the fact that it acts as a hepatic protector, causes haematological regulation and has the disintoxication and immune-modulation effects

Ultrasound and Microbubbles Promote the Retention of Fluorescent Compounds in the Small Intestine

Focused ultrasound (US) is a novel means to increase the passage of medication through the wall of the small intestine. The purpose of this study was to determine whether US and microbubbles (MBs) can facilitate delivery of macromolecular therapeutic agents across the intestinal epithelium in vitro and in vivo. In vitro experiments involved delivery of compounds across a cell monolayer, namely Caco-2 cells cultured on ThinCert filters. The cells were cultured for a minimum of 3 weeks to mimic the polarised intestinal epithelium. A suspension of dextran with or without MBs, prepared in growth medium, was introduced into the apical chamber of the ThinCert with a syringe pump through a channel in the centre of a miniature focused US transducer (4 MHz, 1 MPa PNP). Each in vivo experiment involved a tethered endoscopic capsule with an US transducer and a delivery channel inserted into the small intestine of a terminally anaesthetised pig via a surgical stoma. The amount of fluorescent dextran delivered across the Caco-2 monolayer when employing US, MBs and dextran was higher than the amount delivered with dextran alone. With this approach, fluorescent marking of the wall of the small intestine was achieved in vivo by applying US and MBs. Our work indicates that US has potential for application in targeted treatment of gastrointestinal disease and oral drug delivery

Ultrasound mediated delivery of quantum dots from a capsule endoscope to the gastrointestinal wall

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in-vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focussed ultrasound. These findings suggest that the use of focused ultrasound together with microbubbles could play a role in the oral delivery of biologic therapeutics

Ultrasound mediated delivery of quantum dots from a proof of concept capsule endoscope to the gastrointestinal wall

Biologic drugs, defined as therapeutic agents produced from or containing components of a living organism, are of growing importance to the pharmaceutical industry. Though oral delivery of medicine is convenient, biologics require invasive injections because of their poor bioavailability via oral routes. Delivery of biologics to the small intestine using electronic delivery with devices that are similar to capsule endoscopes is a promising means of overcoming this limitation and does not require reformulation of the therapeutic agent. The efficacy of such capsule devices for drug delivery could be further improved by increasing the permeability of the intestinal tract lining with an integrated ultrasound transducer to increase uptake. This paper describes a novel proof of concept capsule device capable of electronic application of focused ultrasound and delivery of therapeutic agents. Fluorescent markers, which were chosen as a model drug, were used to demonstrate in vivo delivery in the porcine small intestine with this capsule. We show that the fluorescent markers can penetrate the mucus layer of the small intestine at low acoustic powers when combining microbubbles with focused ultrasound during in vivo experiments using porcine models. This study illustrates how such a device could be potentially used for gastrointestinal drug delivery and the challenges to be overcome before focused ultrasound and microbubbles could be used with this device for the oral delivery of biologic therapeutics

Mediastinitis after open heart surgery

IMSP Spitalul Clinic RepublicanScopul lucrării: Mediastinita anterioară după operaţii pe cord este asociată cu o rată sporită a morbidităţii, care duce la mărirea costului mediu de spitalizare a acestui contingent de pacienţi. Scopul acestui studiu a fost de a determina predictorii anteriori de dezvoltare a mediastinitei pre-, intra-, şi postoperatorie. Metode: În perioada anilor 2000 – 2012, în Centrul de Chirurgie cardiacă au suportat intervenţie chirurgicală pe cord 3134 pacienţi, dintre care la 46 (1,46%) de pacienţi evoluţia postoperatorie s-a coplicat cu clinică de mediastinită 23 (0.73%) şi infectarea plăgii postoperatorii cu sau fără dehiscenţa sternului 23 (0.73%). Grupul de pacienţi a fost constituit din 31 (67,3%) bărbaţi şi 15 (32,7%) femei, cu vârsta medie de 59 de ani. Preoperatoriu 21 (45%) din ei erau obezi, 8 (17%) aveau diabet zaharat, 31 (67%) bronşită cronică obstructivă. Pentru By-pass aortocoronarian s-a folosit artera toracică internă unilateral (ATI) 21 (45%) şi ATI bilateral la 2 (4%) pacienţi. Timpul intervenţiei chirurgicale a constituit, în mediu 345min. Transfuzii masive postoperatoriu au necesitat doar la 6 (13%) pacienţi. Diagnosticul de mediastinită a fost stabilit la a 5 - 17 zi postoperatoriu. Restabilirea integrităţii sternale cu aplicarea procedeului Robicsek s-a efectuat la 14(30%) pacienţi. Decesul a fost înregistrat la un pacient 1 (2,1%) a 20-a zi postoperator cauzat de mediastinită seropurulentă şi de insuficienţă poliorganică. La 4 pacienţi s-a dezvoltat osteomielită sternală, care a necesitat tratament de lungă durată (3-6 luni). Concluzia: Studiul sugerează că ATI uni sau bilaterale, bronhopneumonia cronica obstructivă, diabetul zaharat, obezitatea, transfuziile masive, timpul îndelungat a operaţiei sunt predicatori importanţi de mediastinită.Background: Mediastinitis is a serious complication of cardiac surgery. It has a significant socioeconomic impact and high morbidity. The purpose of this study was to determine pre-, intra-, and postoperative predictors of mediastinitis. Methods and results: From 3134 consecutive pacients, which underwent cardiac surgery in 2000-2012, forty-six patients (1.46%) developed postoperator mediastinitis 23 (0.73%) and postoperator wound infection with or without dehiscence of the sternum 23 (0.73%). In this group of pacients 31 were men (67,3%) and 15 women (32,7%) of average age 59 years. Preoperative 21 (45%) of them were obes, 8 (17%) suffered of diabetes mellitus and 31 (67%) of chronic obstructive pulmonary disease. As a Coronary Artery Bypass Graft in 21(45%) was used unilateral IMA, and in 2 (4%) cases BIMA. The average duration of surgery was 345min. Massive transfusion after surgery was needed on six patients (13%). Diagnosis of Mediastenitis was established at the 5 - 17 days postoperatively. Restoration of sternal integrity with the Robicsek proceeding was performed in 14 (30%) patients. One patients dead at the 20th day after surgery due to mediastenitis and failure Multiple Organ System Dysfunctions. Four patients developed sternal osteomyelitis, requiring long-term treatment (3-6 months). Conclusion: The present study suggest that uni/ bilateral internal mammary artery grafting, chronic obstructive pulmonary disease, obesity, transfused units and long surgery duration are important predictors of mediastinitis

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat