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Objective: Complications occur in diabetes despite rigorous efforts to control risk factors. Since 2000, the National Development Programme for the Prevention and Care of Diabetes has worked to halve the incidence of amputations in 10 years. Here we evaluate the impact of the efforts undertaken by analyzing the major amputations done in 1997-2007.Research Design and Methods: All individuals with diabetes (n = 396,317) were identified from comprehensive national databases. Data on the first major amputations (n = 9,481) performed for diabetic and nondiabetic individuals were obtained from the National Hospital Discharge Register.Results: The relative risk for the first major amputation was 7.4 (95% CI 7.2-7.7) among the diabetic versus the nondiabetic population. The standardized incidence of the first major amputation decreased among the diabetic and nondiabetic populations (48.8 and 25.2% relative risk reduction, respectively) over 11 years, and the time from the registration of diabetes to the first major amputation was significantly longer, on average 1.2 years more. The cumulative five-year postamputation mortality among diabetic individuals was 78.7%.Conclusions: In our nationwide diabetes database, the duration from the registration of diabetes to the first major amputation increased, and the incidence of major amputations decreased almost 50% in 11 years. Approximately half of this change was due to the increasing size of the diabetic population. The risk for major amputation is more than sevenfold that among the nondiabetic population. These results pose a continuous challenge to improve diabetes care. [ABSTRACT FROM AUTHOR]

This article describes the results of three different study settings where the use of QR codes and XR technologies were tested for medical device training among 132 social and health care professionals. Data from three types of learning events and different contents of training indicated that the professionals considered these novel technologies both beneficial for learning and useful in their working environments for training safe use of medical devices. Based on the collected data, these technologies can be considered prospective options for medical device training.

This descriptive review provides a synthesis of existing literature about the use of extended reality (XR) including virtual (VR) and augmented reality (AR) technology solutions for competence assurance, training and orientation regarding digital skills and medical device training. From the literature, only few original studies were recognized with a study question or aim to assess medical device training as the target of virtual training modalities. XR methods could provide potential useful solutions to improve medical device competence. Based on the literature, it was evident that further studies are required to research the possibilities of XR technologies to improve medical device training.

Medical Device incident reporting is a legal obligation for professional users in Finland. We analyzed all medical device incident reports recorded into the national incident repository from January 2014 to August 2021. Among the total 5,897 records, annual numbers of incident reports varied between 463 and 1,190. Approximately 80% of the medical device incident reports were near misses, 18.7% were person injuries and 1.3% deaths. The number of annual medical device incident reports between hospital districts varied more than expected when related to the population of catchment area. There was a tendency towards lesser reports per population from smaller hospital districts. In conclusion, medical device incident reporting activity of the professional user varied both annually and geographically. A high number of incidents caused person injuries or even death, which arouses safety concerns. A further analysis is required to explore the causes behind our findings.

Medical Device incident reporting is a legal obligation for professional users in Finland. We analyzed all medical device incident reports recorded into the national incident repository from January 2014 to August 2021. Almost 30% of the total of 5,897 recorded incidents were caused by top ten devices, of which electronic health records were the most common (332 incidents). High number of incidents caused by electronic health records arouses safety concerns. A further analysis is required to explore the causes of findings.

Safety checklists have been studied among various surgical patient groups, but evidence of their benefits in neurosurgery remains sparse. Since the implementation of the World Health Organization's Surgical Safety Checklist, their use has become widespread. The aim of this review was to systematically review the state of the literature on surgical safety checklists in neurosurgery. Also, in the new era of robotics and artificial intelligence, there is a need to re-evaluate patient safety procedures in neurosurgery. A systematic review was conducted on PubMed, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, Embase, and MEDLINE for articles published between 2008 and 2016 using MeSH (medical subject heading) terms and keywords describing postoperative complications and surgical adverse events, and some additional searches were carried out until January 2019. Twenty-six original studies or reviews were eligible for this review. They were categorized into studies with patient-related outcomes, personnel-related outcomes, or previous reviews. Checklist use in neurosurgery was found to reduce hospital-acquired infectious complications and to enhance operating room safety culture. Checklists seem to improve patient safety in neurosurgery, although the amount of evidence is still limited. Despite their shortcomings, checklists are here to stay, and new research is required to update checklists to meet the requirements of the transforming working environment of the neurosurgery operating room., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to identify and analyze the characteristics of leadership and management associated with a successful Lean thinking adaptation in healthcare., Design: A systematic literature review was undertaken using electronic databases: PubMed, PubMed Systematic Review, ABI/INFORM, Business Source Complete, Emerald, JBI, and Cinahl. Inclusion criteria were: (i) a description of Lean management or leadership in health care, (ii) a reference to Lean thinking, (iii) a peer-reviewed original research article or a literature review, and (iv) a full text article available in English. Among the 1,754 peer-reviewed articles identified, nine original articles and three systematic reviews met the inclusion criteria. Data on informants, methods, and settings were extracted and collated. Content analysis was used to conduct a review of the nine original studies describing and analyzing the success factors of Lean adaptation. The characteristics of leadership and management were analyzed by using the concept of a managerial windshield that divides leadership and management into four ontological dimensions: activities, style, focus, and purpose, each with typical developmental stages of skills and capabilities. The current study has some limitations: some papers from the journals not indexed in the searched databases may have been overlooked and the literature searches were carried out only for a 5-year period., Findings: Considering the results using the windshield concept emphasizes the philosophy, principles, and tools of Lean thinking. Lean leadership and management factors in health care were mainly conceptualized as skills and capabilities such as problem solving, making changes occur, empowering, communicating, coaching, supporting, facilitating, being democratic, organizational learning, and organizational success, all of which represented middle-stage or advanced managerial skills and capabilities., Practical Implications: A conceptual analysis of systematically reviewed studies of Lean leadership and management point to certain traits as being typical when adapting Lean thinking to health care. The concept of a managerial windshield is useful when categorizing and analyzing essential managerial skills and capabilities for Lean implementation. Findings are beneficial when learning and educating the skills required for Lean transformation in healthcare organizations.

Object: Use of the WHO surgical checklist has been proven to reduce surgical morbidity and mortality, but its effect on surgical complications requiring reoperation has not been previously studied. The aim of this study was to determine whether the use of the WHO surgical checklist would have an impact on the number and causes of neurosurgical complications leading to a reoperation., Methods: The authors retrospectively gathered information on all neurosurgical reoperations using hospital discharge data as well as the operations and procedures registry, and tracked all primary neurosurgical operations (n = 175) preceding a complication-related reoperation from 2007 to 2011. There were a total of 5418 neurosurgical operations during the study period. For further analysis of electronic patient records, the primary operations were divided into 2 groups based on the time of the WHO surgical checklist implementation in the authors' unit: 103 operations before and 72 after the introduction of the checklist. Observed adverse events and reoperations were categorized as preventable or unpreventable, and the actual use of the checklist during each operation was recorded., Results: The overall rate of preventable complication-related neurosurgical reoperations decreased from 3.3% (95% CI 2.7%-4.0%) to 2.0% (95% CI 1.5%-2.6%) after the checklist implementation. The reoperations were mainly due to wound infections, 46% before and 39% after the checklist. All infection-related reoperations proportioned to all neurosurgical operations (2.5% before vs 1.6% after checklist implementation) showed a significant reduction (p = 0.02) after the implementation of the checklist. In particular, there was a significant decrease (p = 0.006) in the rate of preventable infections associated with reoperations, i.e., 2.2% before versus 1.2% after checklist implementation. The overall adherence to checklist use (the "time out" phase) in neurosurgical operations was 78%, and adherence was 70% in primary operations preceding a complication-related reoperation regarded as preventable., Conclusions: The implementation of the WHO surgical checklist in neurosurgery was associated with a decrease in complication-related reoperations, especially those due to preventable infection complications, the majority of which were wound infections. The adherence to checklist use in individual operations after the checklist implementation did not appear to have an impact on the results.

In order to assess the effectiveness and costs of robot-assisted hysterectomy compared with conventional techniques we reviewed the literature separately for benign and malignant conditions, and conducted a cost analysis for different techniques of hysterectomy from a hospital economic database. Unlimited systematic literature search of Medline, Cochrane and CRD databases produced only two randomized trials, both for benign conditions. For the outcome assessment, data from two HTA reports, one systematic review, and 16 original articles were extracted and analyzed. Furthermore, one cost modelling and 13 original cost studies were analyzed. In malignant conditions, less blood loss, fewer complications and a shorter hospital stay were considered as the main advantages of robot-assisted surgery, like any mini-invasive technique when compared to open surgery. There were no significant differences between the techniques regarding oncological outcomes. When compared to laparoscopic hysterectomy, the main benefit of robot-assistance was a shorter learning curve associated with fewer conversions but the length of robotic operation was often longer. In benign conditions, no clinically significant differences were reported and vaginal hysterectomy was considered the optimal choice when feasible. According to Finnish data, the costs of robot-assisted hysterectomies were 1.5-3 times higher than the costs of conventional techniques. In benign conditions the difference in cost was highest. Because of expensive disposable supplies, unit costs were high regardless of the annual number of robotic operations. Hence, in the current distribution of cost pattern, economical effectiveness cannot be markedly improved by increasing the volume of robotic surgery., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: The World Health Organization's surgical safety checklist is designed to improve adherence to operating room safety standards, and its use has been shown to reduce complications among surgical patients. The objective of our study was to assess the impact of the implementation of the checklist on safety-related issues in the operating room and on postoperative adverse events in neurosurgery., Material and Methods: From structured questionnaires delivered to operating room personnel, answers were analyzed to evaluate communication and safety-related issues during 89 and 73 neurosurgical operations before and after the checklist implementation, respectively. From the analyzed operations, 83 and 67 patients, respectively, were included in a retrospective analysis of electronic patient records to compare the length of hospital stay, reported adverse events, and readmissions. In addition, the consistency of operating room documentation and patient records was assessed., Results and Conclusions: Communication between the surgeon and the anesthesiologist was enhanced, and safety-related issues were better covered when the checklist was used. Unplanned readmissions fell from 25% to 10% after the checklist implementation (p = 0.02). Wound complications decreased from 19% to 8% (p = 0.04). The consistency of documentation of the diagnosis and the procedure improved. The use of the checklist improved safety-related performance and, contemporarily, reduced numbers of wound complications, and readmissions were observed.

Background and Aims: Simulators are widely used in occupations where practice in authentic environments would involve high human or economic risks. Surgical procedures can be simulated by increasingly complex and expensive techniques. This review gives an update on computer-based virtual reality (VR) simulators in training for laparoscopic cholecystectomies., Materials and Methods: From leading databases (Medline, Cochrane, Embase), randomised or controlled trials and the latest systematic reviews were systematically searched and reviewed. Twelve randomised trials involving simulators were identified and analysed, as well as four controlled studies. Furthermore, seven studies comparing black boxes and simulators were included., Results: The results indicated any kind of simulator training (black box, VR) to be beneficial at novice level. After VR training, novice surgeons seemed to be able to perform their first live cholecystectomies with fewer errors, and in one trial the positive effect remained during the first ten cholecystectomies. No clinical follow-up data were found. Optimal learning requires skills training to be conducted as part of a systematic training program. No data on the cost-benefit of simulators were found, the price of a VR simulator begins at EUR 60 000., Conclusions: Theoretical background to learning and limited research data support the use of simulators in the early phases of surgical training. The cost of buying and using simulators is justified if the risk of injuries and complications to patients can be reduced. Developing surgical skills requires repeated training. In order to achieve optimal learning a validated training program is needed.

Background: World Health Organisation (WHO) has introduced a surgical safety checklist that has reduced post-operative morbidity and mortality. Prior to national checklist implementation, we assessed its possible impact on the operating room (OR) process, safety-related issues and communication among surgical staff in a high-income country., Methods: In four university and teaching hospitals, a structured questionnaire was delivered to OR personnel involved in consecutive operations over 4-6 weeks before and after the checklist implementation. The questionnaire resembled the WHO checklist and comprised multiple-choice questions relating to performance of safety checks and communication. Anaesthesiologists (A), surgeons (S) and circulating nurses (CN) answered the questions independently. The WHO checklist was modified for national needs., Results: Questionnaires were returned from 1748 operations, 901 before and 847 after the checklist. Patient's identity was more often confirmed (A: 62.7% vs. 84.0%, S: 71.6% vs. 85.5%, CN: 81.6% vs. 94.2%, P < 0.001) and knowledge of names and roles among team members (A: 65.7% vs. 81.8%, S: 71.1% vs. 83.6%, CN: 87.7% vs. 93.2%, P < 0.01) improved with the checklist. Anaesthesiologists and surgeons discussed critical events pre-operatively (A: 22.0% vs. 42.6%, S: 34.7% vs. 46.2%, P < 0.001) more frequently after the checklist. In addition, fewer communication failures (43 vs. 17, P < 0.05) were reported with checklist., Conclusions: The checklist increased OR teams' awareness of patient-related issues, the procedure and expected risks. It also enhanced team communication and prevented communication failures. Our findings support use of the WHO checklist in various surgical fields., (© 2011 The Authors. Acta Anaesthesiologica Scandinavica © 2011 The Acta Anaesthesiologica Scandinavica Foundation.)

New surgical technologies may challenge societal values, and their adoption may lead to ethical challenges. Despite proven cost-effectiveness, obesity (bariatric) surgery and its public funding have been questioned on ethical arguments relating to, for example, the self-inflicted or non-disease nature of obesity. Our aim was to analyze the ethical issues relevant to bariatric surgery. A comprehensive health technology assessment was conducted on bariatric surgery for morbid obesity using the EUnetHTA method, including a fully integrated ethical analysis. The ethical arguments suggesting that obesity should not be surgically treated because it is self-inflicted were rejected. Medicalization of obesity may have both positive and negative effects that impact the various stakeholders differently, thus being difficult to balance. Informing bariatric surgery patients and actively supporting their autonomy is exceptionally important, as the benefits and harms of both obesity and bariatric surgery are complex, and the outcome depends on how well the patient understands and adheres to the life-long changes in eating habits required. Justice considerations are important in organizing surgical treatment of obesity, as the obese are discriminated against in many ways and obesity is more common in socioeconomically disadvantaged populations who might have problems of access to treatments. Obesity should be treated like other diseases in health care, and obesity surgery rationed like other cost-effective treatments. Positive actions to ensure patient autonomy and just access to surgical treatments may be warranted.

Objectives: The World Health Organisation has developed a Surgical Safety Checklist to improve patient safety during surgery. This checklist has reduced postoperative morbidity and mortality. Prior to checklist implementation, we wanted to evaluate how it would fit into the process of otorhinolaryngology-head and neck surgery and whether it would have an impact on the awareness of safety-related issues., Design: A structured questionnaire was addressed to the operating room team after consecutive operations during a 1-month period before and after checklist implementation., Setting and Participants: This study was conducted at the Department of Otorhinolaryngology at the Helsinki University Central Hospital as a part of a multicentre study. Responses were received regarding 288 operations before and 412 after checklist implementation., Main Outcome Measures: The questions concerned patient-related safety checks, teamwork and communication., Results: The checklist improved verification of the patient's identity (P<0.001). Awareness of the patient's medical history, medication and allergies increased (P<0.001). Knowledge of the names and roles among the team members improved. The otolaryngologists and anaesthesiologists discussed possible critical events more often (P<0.001), and postoperative instructions were better recorded after use of the checklist. In addition, the checklist enhanced communication between operation team members., Conclusions: Our study confirms that the Surgical Safety Checklist fits well into the surgical working process in otorhinolaryngology-head and neck surgery improving the sharing of patient-related medical information between team members. Development of a specific checklist for otolaryngology calls for further study., (© 2011 Blackwell Publishing Ltd.)

Aim: This report considers the introduction of new technology and the implications for patient safety., Methods and Discussion: A distinction is made between 'conceptually' new and 'contextually' new technology. The life cycle of technology from development to routine use is discussed and the key role for regulation, health technology assessment, clinical engineering and surveillance in this life cycle considered. The limitations of each of these disciplines are also discussed. Special consideration is given to the needs of developing countries. Case study examples of particular challenges in the safe introduction of technology are presented.

Background: The role of Chlamydia pneumoniae in peripheral atherosclerosis disease and abdominal aortic aneurysm (AAA) remains unclear. Chlamydial lipopolysaccharide (cLPS) detection is a method used conventionally in routine chlamydial diagnosis of gynecological or ophthalmic samples., Methods: We compared cLPS concentrations, as well as other markers of bacterial load, in plaques and sera of patients operated on for carotid artery stenosis (n=110), aorto-occlusive disease (n=22), or AAAs (n=50) at the Helsinki University Central Hospital., Results: The median levels of cLPS in plaques were 2.28, 0.80, and 0.29 ng/ml in AAA, aorto-occlusive disease, and carotid artery stenosis patients, respectively (P<.001, Kruskal-Wallis). cLPS in serum correlated with LPS binding protein levels (Spearman's rho=0.52, P<.001), suggesting that the presence of chlamydiae is sufficient to produce an innate immune response reaction in these patients. Serum inflammatory markers interleukin 6 and highly sensitive C-reactive protein also correlate with cLPS (Spearman's rho=0.42 and 0.51, respectively, P<.001)., Conclusions: cLPS is present in arterial disease, and the potential role of C. pneumoniae in the pathogenesis of both peripheral atherosclerosis disease and AAA should not be forgotten. cLPS has a positive correlation with serum inflammatory markers, but this is no proof of a causal association.

Morbid obesity is associated with severely invalidizing symptoms and a strong stigma, which restrict the management of daily life. The handicaps of morbid obesity are so severe that patients are ready to accept even inconvenient adverse effects or high risks from the treatment. Seeking antiobesity surgery is mainly done for health reasons, but is perceived to have a broad effect on functional capacity, self-image as well as on mental and social well-being. By the help of anti-obesity surgery, many patients not only gain control over eating, but also over other fields of life.

Attitude to obesity determines the attitude to antiobesity surgery: is obesity a disease among other diseases belonging to the public health care, or a characteristic resulting from living habits, remaining under the person's own responsibility? Antiobesity surgery requires supporting the patients' right to self-determination. Other treatments for obesity should be available, and this procedure necessitating permanent adjustments of living habits requires sufficient advance preparation. The patient's guarantee governing the treatment of obesity as a whole seems relevant. Assessment of the need for surgery is, however, difficult and the benefits and disadvantages differ among the various stakeholders.

Evidence for the effectiveness of surgical treatment of morbid obesity on life span, quality of life and associated diseases proves it an applicable alternative for the morbidly obese in cases where other means of controlling obesity have remained ineffective. The operation causes significant weight reduction even within a 15-year follow-up. Surgical mortality after an endoscopic operation is usually less than 0.5%. After the operation, patients fairly often experience various symptoms of the digestive tract. Common complications include various infections and functional disturbances associated with the band.

Although intervention in obesity on a consultation visit, i.e. brief intervention, will only affect a portion of patients, it can reach large numbers of patients. Basic care of obesity, i.e. patient education in a group, leads to an average weight loss of 3 to 5 kg within one to two years. Basic care should be offered to patients having a condition that requires weight reduction during the treatment. In morbid obesity, surgical treatment should be promoted in Finland, although it can only be applied to a minor fraction of those requiring antiobesity treatment. Self-motivated weight control should thus be encouraged.

The number of and demand for surgical treatments of morbid obesity are quickly increasing in Finland. The resources and action models differ regionally. The position of antiobesity surgery among antiobesity treatments should be defined more clearly than is now the case in Finland. Also a decision should be made how these operations are included in the patient's treatment guarantee. There should be a public discussion on how to centralise the operations into sufficiently large units of expertise and availability of the treatment in various parts of Finland must be guaranteed. Treatment chains should be standardized, at the same time ascertaining adequate expertise of various health care providers.

Objective: Myocardial gene and cellular therapies have revived the use of porcine ischemic heart models. Commonly applied ameroid-obstruction produces inconsistent coronary stenoses and myocardial lesions, whereas abrupt coronary occlusion causes arrhythmias and sudden death. To produce a constant myocardial lesion after adaptation to ischemia, we surgically modified the ameroid-model by ligation. As a pilot study for further cell therapy research, the spontaneous myocardial response is described., Materials and Methods: Simultaneously with ameroid application, a loose loop of nonabsorbable thread was placed around the left circumflex artery (LCx) on 11 domestic piglets. Three weeks later, the loop was tightened. Coronary arteriograms with Rentrop collateral grading from 0 to 3, and 99mTc-single photon emission computerized tomography studies were performed 1 to 5 wk after ligation. At autopsy, the hearts were analyzed macroscopically, histologically, and with von Willebrandt factor-staining., Results: LCx-banding was well-tolerated in nine animals, of which angiographic occlusion was gained in eight. Postmortem analysis revealed a 5 to 10 cm(2) transmural or subendocardial lateral myocardial infarction in all except one heart. One week after occlusion, LCx showed well-developed collateral filling (Rentrop-grade 2.7 +/- 0.4), which remained unchanged at 5 wk. On single photon emission computerized tomography-scans, lateral wall perfusion increased spontaneously between 1 and 5 wk (P = 0.02), and von Willebrandt factor revealed clusters of neovascularization at the borders of infarct areas., Conclusions: This new modification of ameroid model standardizes myocardial lesion, which might reduce animal number in preclinical studies, thus having ethical aspect. The remarked potential for spontaneous recovery in ischemic porcine myocardium should be considered in preclinical therapeutic studies.

The main extracellular matrix components of the lung, type I and III collagens, were studied in chronic allograft rejection developing in a porcine heterotopic bronchial transplantation model. Specific porcine complementary DNA probes were constructed for detection of the expression of type I and III procollagen messenger RNAs in the bronchial wall structures and in the obliterative plug by in situ hybridization. In autografts, and in allografts immunosuppressed with 40-O-(2-hydroxyethyl)-rapamycin, cyclosporine A, and methylprednisolone, no histological changes of obliterative bronchiolitis (OB) developed, and the number of fibroblast-like cells expressing type I and III procollagen mRNA remained low. In nontreated allografts obliterating within 21 d, a preponderance of fibroblast-like cells showing positivity for type III procollagen mRNA existed in the obliterative plug and bronchial wall. This study shows for the first time the temporal and spatial activation of type I and III procollagen genes during the course of obliterative bronchiolitis. The number of cells expressing procollagen III mRNA increased parallel to developing obliteration and fibrosis in nontreated allografts, whereas autografts and immunosuppressed allografts exhibited no such trend. This finding suggests a positive association between type III collagen mRNA expression in fibroblast-like cells and development of obliterative bronchiolitis.

Background: Because epithelial cells are targets of alloimmune injury leading ultimately to airway obliteration, we tested whether epithelial re-growth could prevent obliterative airway disease (OAD) in orthotopic tracheal allografts., Methods: Brown Norway tracheal segments were orthotopically transplanted into nonimmunosuppressed Lewis rats. Allografts were removed on days 2-10 (n=13), 30 (n=4), and 60 (n=5) for histology, computerized morphometry (obliteration), and immunohistochemical detection of mononuclear cells, smooth muscle alpha-actin, and tissue phenotype. Normal tracheas, host tracheas, and heterotopically transplanted allografts served as controls., Results: Orthotopic allografts removed on days 2-10 exhibited epithelial damage and re-growth and mononuclear cell infiltration. On days 30 and 60, partially ciliated cuboidal or attenuated epithelium completely covered the lumen. Although mononuclear cells declined, numerous T cells with a high CD4/CD8 ratio were found in the epithelium till day 60. Orthotopic allograft epithelium expressed donor phenotype on day 7, but recipient phenotype on days 30 and 60. Despite subepithelial alpha-actin positive myofibroblast proliferation, obliteration did not progress from day 7 to 30 and 60 (35, 30, and 33%, respectively). Although more than in normal or host tracheas, the obliteration in orthotopic allografts on days 30 and 60 was significantly less (P<0.001) than in heterotopic allografts., Conclusions: We describe, for the first time, longterm patency of fully histoincompatible orthotopic tracheal allografts in nonimmunosuppressed rats. Despite acute alloimmune injury and induction of myofibroblast proliferation, epithelial re-growth from the host limited the progression of OAD, thus emphasizing the role of epithelium in the control of airway obliteration.

Background: Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS)., Methods: Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105., Results: Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05)., Conclusions: Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Background: Graft vascular disease (GVD) is an incompletely understood process and the primary cause of late allograft failure. A nonhuman primate model was established to study the progression of GVD by using serial intravascular ultrasound (IVUS)., Methods: Aortic allografts were transplanted below the inferior mesenteric arteries (IMA) into 6 rhesus monkeys. Removed and re-implanted aortic segments between renal arteries, and the inferior mesenteric arteries served as autografts. IVUS was performed at days 0, 24, 52, 80, and 98 after transplantation. Vessel area (VA) and lumen area (LA) were measured from each cross-section at 0.5 mm intervals. Intimal index (II=100x (VA-LA/VA)) and corresponding vessel volumes were calculated for the whole grafts. Histologic features were assessed from autopsy samples using computerized morphometric method and a score from 0 to 3 for GVD (0=none, 3=severe)., Results: In allografts, vessel volume and luminal volume decreased significantly (P<0.05 for both) and the intimal index increased from 12% to 59% by day 98. These parameters remained unchanged in autografts. Histologic analysis of allografts showed concentric intimal hyperplasia and scattered mononuclear cell accumulations, whereas the autografts had only occasional eccentric intimal changes. The GVD-scores were significantly higher in allografts than in autografts (median 3 vs. 1, P=0.042)., Conclusions: We introduce a nonhuman primate model of GVD that enables serial IVUS assessments of multiple parameters of GVD. Concentric intimal proliferation and decrease of vessel dimensions was observed in allografts as a consequence of alloimmunity. This is a potential new model for studying new therapies to prevent GVD or halt its progression.

The main cause of mortality following lung transplantation is chronic rejection, manifesting morphologically as obliterative bronchiolitis (OB). It has been suggested that damage to the respiratory epithelium initiates proliferation of mesenchymal cells, leading to dense collagenous scarring in small airways. Inducible nitric oxide synthase (iNOS) is strongly expressed in the damaged epithelium in human OB, along with high levels of peroxynitrite, suggesting that endogenous NO mediates the epithelial destruction. To examine further the role of iNOS in this process, heterotopic airway implants were studied in rats, an acknowledged disease model. Specimens of iso- or allografted trachea, collected 3-60 days after implantation, were processed for histology and immunocytochemistry for iNOS and, as a marker of peroxynitrite formation, nitrotyrosine. In both iso- and allografts at the earliest stage (day 3), ischaemia was associated with severe epithelial damage or loss. These changes progressed until day 7 and were accompanied by strong expression of iNOS and nitrotyrosine in epithelial cells. In isografts, epithelial recovery was seen, with abundant iNOS immunoreactivity but little nitrotyrosine. In contrast, the epithelium in allografts did not regenerate and progressive inflammation and fibroproliferation occurred until complete obliteration of the tracheal lumen at day 60. The fibroproliferation was associated with changes in morphology of fibroblasts that were accompanied by alterations in their iNOS expression. iNOS immunoreactivity was dense in the plump fibroblasts of early lesions, in some cases as early as post-operative day 5, but very weak in elongated fibroblasts in totally occluded grafts. The intensity of immunoreactivity for nitrotyrosine corresponded to that of iNOS. These results indicate a dual role for NO in the airway obliteration that follows transplantation, through destruction of epithelium and stimulation of fibroblast activity., (Copyright 2000 John Wiley & Sons, Ltd.)

Background: In our swine model of obliterative bronchiolitis preventing obliteration by the standard immunosuppression with cyclosporine, methylprednisolone, and azathioprine was not successful. The purpose of this study was to test the ability of a new immunosuppressive regimen to prevent alloimmune reaction and obliteration of the allografts. This regimen includes the novel macrolide SDZ RAD, i.e., 40-O-(2hydroxyethyl)-rapamycin., Methods: Donor lung allografts of 1 cm3 were implanted sub-cutaneously into 11 random-bred non-related domestic pigs receiving daily oral cyclosporine (10 mg/kg) and methylprednisolone (20 mg). In addition, the animals received either oral azathioprine (2 mg/kg) (Group 1) or oral SDZ RAD (1.5 mg/kg) (Group 2). Histologic alterations were graded from 0 to 3 based on repeatedly removed implants during a follow-up period of 3 months., Results: Total epithelial destruction and permanent luminal obliteration occurred within 37 days in Group 1. After an initial grade of 2.3+/-0.3 destruction, epithelial recovery was evident in Group 2 (P < 0.01), and the bronchi stayed patent. Cartilaginous destruction was milder in Group 2 (P < 0.05) than in Group 1, but chondrocytic proliferation was more intense (P < 0.05). Alveolar tissue and native structures of the bronchial wall were destroyed in Group 1, but preserved in Group 2 with total recovery after a mild-grade initial necrosis., Conclusions: Unlike the standard triple therapy, SDZ RAD combined with cyclosporine and methylprednisolone preserves the pulmonary allografts and prevents epithelial destruction and subsequent luminal obliteration. This suggests that this regimen might efficiently suppress obliterative bronchiolitis and improve long-term results in lung transplant recipients.

We investigated the efficacies of sirolimus (rapamycin) and cyclosporine for inhibition of graft vascular disease (GVD) in cynomolgus monkey recipients of aortic allografts. Increases in arterial intimal thickening in the midgraft (six consecutive cross-sections) after transplantation were quantified by serial intravascular ultrasound (IVUS) from day 21 to day 105. These data enabled correlations between changes in intimal indexes [II = (intimal area/vessel area) x 100] and trough levels of sirolimus and cyclosporine to be determined. Eighteen recipients received no immunosuppression for 6 weeks to allow alloimmune injury to occur. On day 45, monkeys were treated daily with sirolimus (n = 6) or cyclosporine (n = 6); six monkeys remained untreated. II increased significantly from day 63 to day 105 in untreated monkeys and monkeys treated with cyclosporine, whereas monkeys treated with sirolimus did not have a significant increase in II (P = 0.008, P = 0.006, P = NS; paired t-test). The change in II from days 63 to 105 was significantly greater in untreated monkeys compared to sirolimus-treated monkeys (P = 0.13; one-way ANOVA, P = 0.012 Tukey's post hoc test); other post hoc pairwise comparisons were not significant. Mean sirolimus and cyclosporine levels +/- SEM were 43 +/- 7 ng/ml and 562 +/- 20 ng/ml, respectively. Sirolimus trough levels, but not cyclosporine levels, correlated inversely with changes in II from day 42 to 105 (r2 = 0.73, P = 0.03). This non-human primate study shows that inhibition of intimal thickening by sirolimus depends on trough levels and provides the rationale for clinical trials of sirolimus for the control of GVD in organ transplant recipients.

Background: Unprocessed ultrasound radiofrequency (RF) signal analysis has been shown to distinguish different tissue structures more reliably than gray-scale interpretation of conventional ultrasound images., Methods and Results: The objective of this study was to test the feasibility of in vivo intravascular ultrasound (IVUS) RF signal analysis in an animal model of allograft rejection. Six cynomolgus monkeys underwent transplantation of 3-cm aortic allograft segments distal to the renal arteries from immunologically mismatched donors. IVUS imaging with a 30-MHz system was performed 84 to 105 days after the operation. RF signals were acquired from cross sections of the recipient and the allograft aortas in real time with a digitizer at 500 MHz with 8-bit resolution. Sixty-five cross sections and 68 regions of interest (31 in host aorta and 37 in allograft) were analyzed in the adventitial layer with a total number of 8568 vectors processed. For each region of interest, a weighted-average attenuation was calculated on the basis of the attenuation and length for each individual vector. Histological examination was performed at every cross section imaged by IVUS. When the gray-scale images of conventional IVUS scored by an independent observer were compared, no distinction between adventitia of the native aorta and allograft was possible. Analysis of the average RF backscatter power also showed no significant difference (70.32+/-3.55 versus 70.72+/-3.38 dB). However, the average attenuation of allografts was significantly lower than that of the host aortas (2.64+/-1.38 versus 4.02+/-1.16 dB/mm, P<0.001). Histology demonstrated a marked adventitial inflammatory response in all allografts, with no inflammation observed in the host aortas., Conclusions: In vivo IVUS tissue characterization can be performed during routine imaging. In this model of transplant vasculopathy, RF attenuation measurements were more sensitive than visual or quantitative gray-scale analysis.

Background: Obliterative bronchiolitis (OB), the major long-term complication of lung transplantation, has thus far lacked a good large-animal model. Our goal was to develop such a model on the basis of previous rodent models with tracheal implants., Methods: Fragments of pulmonary tissue with structures of terminal bronchi were subcutaneously transplanted to four random-bred domestic piglets. Each animal received 10 autograft and 10 allograft implants. The histologic findings were graded from 0 to 3 for implants harvested repeatedly over 2 months., Results: In autografts, partial destruction of the respiratory epithelium and gradual luminal obliteration as well as mild damage to the cartilage and the bronchial wall underwent rapid reversal after initial ischemic injury. In the allografts, epithelial destruction and gradual obliteration were total within 14 days, the difference being statistically significant (P<0.05) in both. The histologic features of the obliterative plug were similar to those of human OB. In the allografts, cartilaginous destruction and pericartilaginous inflammation increased gradually to severe levels, significantly worse than in the autografts (P<0.05). Necrosis and inflammation of the bronchial wall were also more severe in the allografts (P<0.05)., Conclusions: At the end of follow-up, all autografts were vital, whereas the allografts were almost totally rejected and were without native structures. All bronchi in the allografts exhibited accelerated obliteration with histologic features characteristic of human OB, thus providing a model for research into OB and its prevention.

Uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), presently called UDP-glycosyltransferases, catalyse the detoxification of many toxic and carcinogenic compounds. Glucuronidation is also a major metabolic pathway for numerous drugs. The UGT1A6 gene (formerly known as UGT1*06 and UGT1A1) has been suggested to belong to the aryl hydrocarbon (Ah) gene battery, which consists of several genes encoding for drug-metabolising enzymes regulated by dioxin and other ligands of the Ah receptor. In this study, we analysed the localisation of UGT1A6 expression in rat liver by in situ hybridisation to mRNA. Two different RNA probes were used, one which was specific to UGT1A6 and the other against the C terminal sequence shared by all UGT1 genes. In this study, no UGT1A6 mRNA was detected in the control animals. However, other gene(s) of the UGT1 family were expressed in the perivenous region surrounding the central veins as detected by hybridisation with the probe against the common region of the UGT1 genes. Treatment with the lower dose (5 mg/kg) of 3-methylcholanthrene (3MC) induced expression of UGT1A6 perivenously. Treatment with the higher dose (25 mg/kg) of 3-Methylcholanthrene resulted in a more panacinar expression pattern. In contrast to the perivenous induction observed with 3-methylcholanthrene, treatment with 15 mg/kg of beta-naphthoflavone (BNF) resulted in strong induction in the periportal region. The results reveal an inducer-specific pattern of UGT1A6 expression similar to that demonstrated earlier for other Ah battery genes, namely CYP1A1, CYP1A2, GSTYalpha and ALDH3. The finding further supports the notion that common factors regulate the regional hepatic expression of Ah battery genes.