Search

Objectives The PROSE trial purpose is to investigate whether the incidence of thromboembolic—related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc.—On-X) compared with a previous generation mechanical prosthesis (St Jude Medical—SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. Methods The PROSE study was conducted in 28 worldwide centres and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors. Results The total patient population (855) incorporated On-X population (462) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic and mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. Conclusions The preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations.

Objective Although the results of aortic valve replacement are well documented for industrialized countries, the outcome in patients with rheumatic aortic valve disease in low- to middle-income countries is less well explored. The aim of this study was to determine the long-term survival and clinical outcomes after isolated aortic valve replacement in patients with rheumatic heart disease in a Sub-Saharan country where follow-up of indigent patients is often challenging. Methods A retrospective review of 969 aortic valve replacements performed between 2003 and 2013 was conducted at Cape Town's Groote Schuur Hospital. Patients who underwent concomitant procedures (n = 664) or had nonrheumatic valve pathology (n = 185) were excluded. The mean age of the rheumatic cohort (n = 121) was 43.1 ± 11.6 years with a mean follow-up period of 6.14 ± 3.44 years. The primary end points were survival and valve-related complications. Results A 15% cardiac- or valve-related 10-year mortality after receiving a mechanical prosthesis corresponded with a significantly higher mortality rate than that of a matched population. Overall cumulative survival at 1, 5, and 10 years was 93.5% (87.0-96.9), 86.4% (78.4-91.8), and 78.1% (67.5-86.0), respectively, and the corresponding cumulative freedom from combined thromboembolism and bleeding was 94.4% (88.2-97.5), 87.4% (79.4-92.5), and 86.1% (77.9-91.6), respectively. Conclusions In low- to middle-income countries, with their unique mix of indigent and “First World” patients, rheumatic heart disease still accounts for a significant proportion of patients requiring isolated aortic valve replacement. Although mechanical prostheses are often selected in these young adults, survival remains suboptimal. Major bleeding and thromboembolic events account for the majority (77%) of the reported valve-related complications.

ObjectivesThe PROSE trial purpose is to investigate whether the incidence of thromboembolic – related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc. – On-X) compared with a previous generation mechanical prosthesis (St Jude Medical – SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. MethodsThe PROSE study was conducted in 29 worldwide centres and incorporated 854 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors.ResultsThe total patient population (854) incorporated On-X population (461) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic & mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. ConclusionsThe preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations.

In the face of the novel coronavirus pandemic, the impact of COVID-19 infection has disrupted cardiothoracic surgical services globally. A risk-adjusted approach to restructuring the delivery of cardiothoracic surgical services has been proposed in accordance with international guidance to ensure that the surgical standard of care is maintained in the practice of adult and paediatric cardiac surgery, as well as thoracic surgery. The potential influx of COVID-19 patients with cardio-respiratory complications requiring intensive care management and associated surgical procedures falling within the gamut of the thoracic surgeon, is considered. Finally, the protection of healthcare workers, in particular the surgical team exposed to aerosolising procedures, is outlined.

Lung transplantation (LT) is a robust therapy for advanced lung disease, which offers recipients extended and good-quality survival. In South Africa (SA), patients have historically had limited access to this therapy, particularly if unfunded. LT has been used as a successful therapeutic intervention for a wide variety of end-stage pulmonary parenchymal and vascular diseases, but the most common diseases that lead to LT are chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, alpha-1-antitrypsin deficiency and pulmonary arterial hypertension. Timing of referral for LT can be challenging and is disease specific, influenced by the rate of progression of the disease, the development of associated comorbidities, and access and response to advanced therapies. Advances in recipient and donor selection, surgical technique and postoperative management have improved early survival, but mortality remains higher than for other solid organ transplants. Rejection and infection remain major causes of early posttransplant death, while chronic rejection is the major cause of death after the first year. Survival is heavily influenced by the underlying lung disease. In this review, we summarise the indications and contraindications for LT, remind pulmonologists of the availability of this therapy in SA and offer guidelines for the timely referral of suitable candidates.

More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 ± 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 ± 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries.

No Abstract

Pulmonary arterial hypertension rarely develops in patients with simple transposition of the great arteries who undergo neonatal surgical correction. We describe a young male patient who was diagnosed with severe pulmonary arterial hypertension 14 years after neonatal arterial switch surgery. The relevant literature is briefly reviewed. Clinicians should be aware of this rare, late, and potentially life-threatening condition. Continued long-term follow up of these patients should be provided. Early diagnosis and treatment with combination therapy may improve outcomes

The potato (Solanum tuberosum L.) cultivar 'SpuntaG2' contains a single copy of the Bacillus thuringiensis (Bt) cry1Ia1 gene and controls potato tuberworm (Phthorimaea operculella Zeller, Lepidoptera: Gelechiidae). Two potato cultivars and two breeding lines were crossed with SpuntaG2 creating four populations used to study cry1Ia1 segregation and efficacy. The cry1Ia1 gene segregated in each of the four populations with a 1:1 ratio. All progeny that were polymerase chain reaction positive for the cry1Ia1 gene had no surviving larvae and no leaf mining in detached leaf assays after 72 h. These results support previous evidence that SpuntaG2 carries a single copy of the cry1Ia1 gene and that transmission of the transgene from parent to progeny is not restricted and follows expected Mendelian segregation ratios. Based on detached leaf assays, the efficacy of the cry1Ia1 gene is retained through sexual transmission. If the SpuntaG2 cry1Ia1 insertion event is deregulated for commercial use, SpuntaG2 could be used for conventional breeding and the progeny carrying the SpuntaG2 event would also be available for commercial use.

‘SpuntaG2’ is a transgenic potato (Solanum tuberosum) cultivar that contains the cry1Ia1 gene for resistance to potato tuber moth (Phthorimaea operculella), which is a serious pest of potato in many parts of the world. Previous studies have characterized ‘SpuntaG2’ at the molecular level and evaluated it for safety as a human food source. The objective here was to determine the efficacy of ‘SpuntaG2’ against the potato tuber moth in the field and in storage and to evaluate its agronomic performance. Efficacy trials at seven South African locations over 5 years indicated that ‘SpuntaG2’ gave complete control of potato tuber moth in the field and storage. The agronomic performance (tuber size and yield) of ‘SpuntaG2’ was not statistically different from ‘Spunta’ or was better than ‘Spunta’ at all locations/years with two exceptions. Three years of trials in Michigan further support these conclusions. Evaluations done during the 2006–07 South African season showed that ‘SpuntaG2’ did not differ from non-transgenic ‘Spunta’ for the following traits: maturity, growth habit, eye morphology, tuber size distribution, tuber shape, skin and flesh color, growth cracks, internal defects, specific gravity, chip color, cooking quality, disease resistance, and pollen fertility. Based on the results of these trials, it was concluded that ‘SpuntaG2’ provides the agronomic performance of ‘Spunta’ with the added benefit of resistance to potato tuber moth.

The transgenic potato ‘SpuntaG2’ (Solanum tuberosum), which is resistant to potato tuber moth (Phthorimaea operculella), was subjected to protein safety evaluations including protein equivalency tests for the Cry1Ia1 protein from ‘SpuntaG2’ and bacterially produced Cry1Ia1, toxicity and allergenicity evaluations of Cry1Ia1 protein, and compositional equivalency of ‘SpuntaG2’ compared with non-transgenic ‘Spunta’. Western blot analysis and biological activity assays showed molecular and functional equivalency between ‘SpuntaG2’-derived Cry1Ia1 protein and bacteria-derived Cry1Ia1 protein. Comparison of the Cry1Ia1 amino acid sequence to known amino acid sequences revealed no significant homology to known toxins or known allergens. Acute toxicity studies using rodents were used to calculate an acceptable daily intake (ADI) value of 20 mg·kg−1 body weight per day. The ADI value was then used to calculate a margin of exposure (MOE) of 2,222,222, which is more than 22,000 times greater than the commonly used target MOE of 100. Digestibility and thermostability assays determined that Cry1Ia1 was fully digested within 30 s of exposure to pepsin and inactive after 3 to 4 minutes at 100 °C, indicating that it would not be a potential allergen. Compositional analyses revealed no difference between ‘SpuntaG2’ and non-transgenic ‘Spunta’. These results strongly indicate that the Cry1Ia protein and the transgenic potato ‘SpuntaG2’ is not a human health risk.

Potato tuber moth (Phthorimaea operculella) is a serious pest of potatoes in tropical and subtropical regions of the world, including South Africa. The cry1Ia1 gene (from Bacillus thuringiensis) under the control of the 35S cauliflower mosaic virus promoter was transformed into the potato (Solanum tuberosum) cultivar Spunta to develop a cultivar with resistance to potato tuber moth for release in South Africa. Two transformation events, ‘SpuntaG2’ and ‘SpuntaG3’, were selected and subjected to extensive molecular analyses as required by the regulatory agencies of South Africa. Southern hybridization experiments indicated that ‘SpuntaG2’ and ‘SpuntaG3’ had one and three copies of the cry1Ia1 gene, respectively, and that the gene insertion was stable through multiple clonal generations. Furthermore, the sequence of the cry1Ia1 gene in ‘SpuntaG2’ was compared with the known sequence of the cry1Ia1 gene and found to be identical. Polymerase chain reaction (PCR) amplification using primers for plasmid “backbone” genes demonstrated that ‘SpuntaG2’ contained no backbone plasmid genes, whereas ‘SpuntaG3’ contained several backbone plasmid genes. Therefore, further analyses were limited to ‘SpuntaG2’, and event-specific primers were developed for this cultivar. Analysis of the left and right border regions in ‘SpuntaG2’ demonstrated that the insertion of the cry1Ia1 gene did not disrupt any functional genes nor did it create new open reading frames that encoded proteins with a significant match to the non-redundant sequence database queried by the BLASTP program. Enzyme-linked immunoabsorbent assays (ELISA) tests indicate that the cry1Ia1 gene was expressed at a mean concentration of 2.24 μg·g−1 fresh weight in leaf tissue and 0.12 μg·g−1 fresh weight in tubers. This study demonstrates the extensive molecular characterization that is necessary to apply for deregulation of a genetically modified crop and these data have been used in a regulatory package for the general release of ‘SpuntaG2’.

Reply to Mankahla N, Dlamini S, Taunyane IC, Maqungo S, Cairncross L, Chiliza B. Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. S Afr Med J 2018;108(3):151. https://doi.org/10.7196/SAMJ.2018.v108i3.13114.

The paper analyses the development of newly started bioscience firms in terms of their capabilities and changes in their business models. The study consists of eight retrospective case studies stemming from their foundation over a period of 5–15 years. Empirically the paper finds that all the firms quickly develop a technological capability at the time of their foundation, and over time all firms added distinctly new business capabilities. Seven firms radically changed their business models by identifying and exploiting new opportunities by drawing on their existing business capability combined with a new, different technological capability. The initial technological capability – the firms' ‘ticket to entry’– does not seem to be relevant to explain the process of firm development. These initial technological capabilities are surprisingly seldom leveraged within the cumulative process of opening up additional opportunities and business models. The paper concludes by creating a model and discusses some reasons for the findings.

Prosthetic heart valves epitomize both the triumphant advance of cardiac surgery in its early days and its stagnation into a retrospective, exclusive first world discipline of late. Fifty-two years after the first diseased heart valve was replaced in a patient, prostheses largely represent the concepts of the 1960s with many of their design-inherent complications. While the sophisticated medical systems of the developed world may be able to cope with sub-optimal replacements, these valves are poorly suited to the developing world (where the overwhelming majority of potential valve recipients reside), due to differences in age profiles and socio-economic circumstances. Therefore, it is the latter group which suffered most from the sluggish pace of developments. While it previously took less than 7 years for mechanical heart valves to develop from the first commercially available ball-in-cage valve to the tilting pyrolytic-carbon disc valve, and another 10 years to arrive at the all-carbon bi-leaflet design, only small incremental improvements have been achieved since 1977. Similarly, bioprosthetic valves saw their last major break-through development in the late 1960s when formalin fixation was replaced by glutaraldehyde cross linking. Since then, poorly understood so-called 'anti-calcification' treatments were added and the homograft concept rediscovered under the catch-phrase 'stentless'. Still, tissue valves continue to degenerate fast in younger patients, making them unsuitable for developing countries. Yet, catheter-delivered prostheses almost exclusively use bioprosthetic tissue, thereby reducing one of the most promising developments for patients of the developing world into a fringe product for the few first world recipients. With tissue-engineered valves aiming at the narrow niche of congenital malformations and synthetic flexible leaflet valves being in their fifth decade of low-key development, heart valve prostheses seem to be destined to remain an unsatisfying and exclusive first world solution for a long time to come.

Christiaan (Chris) Neethling Barnard was born in South Africa and qualified in medicine at the University of Cape Town in 1946. Following surgical training in South Africa and the USA, Barnard established a successful open-heart surgery program at Groote Schuur Hospital and the University of Cape Town in 1958. In 1967, he led the team that performed the world's first human-to-human heart transplant. Although the first heart transplant patient survived only 18 days, four of Groote Schuur hospital's first 10 patients survived for more than one year, two living for 13 and 23 years, respectively. This relative success amid many failures worldwide did much to generate guarded optimism that heart transplantation would eventually become a viable therapeutic option, Barnard then developed the operation of heterotopic heart transplantation (the socalled "piggy-back" transplant), which had some advantages in the pre-cyclosporine era when immunosuppressive therapy was limited. His group was the first to successfully transport donor hearts using a hypothermic perfusion storage device in 1981. Several studies on the haemodynamic and metabolic sequelae of brain death were carried out in his Department's cardiovascular research laboratories at the University of Cape Town, and the concept of hormonal replacement therapy in organ donors was developed. An active heart transplant program still continues in the Chris Barnard Division of Cardiothoracic Surgery at Groote Schuur Hospital and the University of Cape Town, but the thrust of clinical activity within the Division and the research within its state-of-the-art cardiovascular research laboratories is now directed towards valvular and ischaemic heart diseases, which are common in the African population.

Pediatric cardiac services are too expensive for most developing nations. Problems other than cardiac disease take priority when it comes to budget allocations. Poor health infrastructure and referral systems, malnutrition, and the HIV/AIDS pandemic aggravate the situation, and the increasing economic divide is threatening what services do exist. We highlight how the practice of pediatric cardiac surgery in South Africa compares with first-world standards and outline some of the problems faced by pediatric cardiac services in developing nations.

An urgent and steadily increasing need exists world-wide for a greater supply of donor thoracic organs. Xenotransplantation offers the possibility of an unlimited supply of hearts and lungs that could be available electively when required. However, anti-body- mediated mechanisms cause the rejection of pig organs transplanted into non-human primates, and these mechanisms provide major immunologic barriers that have not yet been overcome. Having reviewed the literature on xenotransplantation, we present a number of conclusions on its present status with regard to thoracic organs, and we make a number of recommendations relating to eventual clinical trials. Although pig hearts have functioned in heterotopic sites in non-human primates for periods of several weeks, median survival of orthotopically transplanted hearts is currently ,1 month. No transplanted pig lung has functioned for even 24 hours. Current experimental results indicate that a clinical trial would be premature. A potential risk exists, hitherto undetermined, of transferring infectious organisms along with the donor pig organ to the recipient, and possibly to other members of the community. A clinical trial of xeno-transplantation should not be undertaken until experts in microbiology and the relevant regulatory authorities consider this risk to be minimal. A clinical trial should be considered when approximately 60% survival of life-supporting pig organs in non-human primates has been achieved for a minimum of 3 months, with at least 10 animals surviving for this minimum period. Furthermore, evidence should suggest that longer survival (.6 months) can be achieved. These results should be achieved in the absence of life-threatening complications caused by the immunosuppressive regimen used. The relationship between the presence of anti-HLA antibody and anti-pig antibody and their cross-reactivity, and the outcome of pig-organ xenotransplantation in recipients previously sensitized to HLA antigens require further investigation. We recommend that the patients who initially enter into a clinical trial of cardiac xenotransplantation be unacceptable for allotransplantation, or acceptable for allotransplantation but unlikely to survive until a human cadaveric organ becomes available, and in whom mechanical assist-device bridging is not possible. National bodies that have wide-reaching government-backed control over all aspects of the trials should regulate the initial clinical trial and all subsequent clinical xenotransplantation procedures for the foreseeable future. We recommend coordination and monitoring of these trials through an international body, such as the International Society for Heart and Lung Transplantation, and setting up a registry to record and widely disperse the results of these trials. Xenotransplantation has the potential to solve the problem of donor-organ supply, and therefore research in this field should be actively encouraged and supported.

The potato (Solanum tuberosum L.) cultivar 'SpuntaG2' contains a single copy of the Bacillus thuringiensis (Bt) cry1Ia1 gene and controls potato tuberworm (Phthorimaea operculella Zeller, Lepidoptera: Gelechiidae). Two potato cultivars and two breeding lines were crossed with SpuntaG2 creating four populations used to study cry1Ia1 segregation and efficacy. The cry1Ia1 gene segregated in each of the four populations with a 1:1 ratio. All progeny that were polymerase chain reaction positive for the cry1Ia1 gene had no surviving larvae and no leaf mining in detached leaf assays after 72 h. These results support previous evidence that SpuntaG2 carries a single copy of the cry1Ia1 gene and that transmission of the transgene from parent to progeny is not restricted and follows expected Mendelian segregation ratios. Based on detached leaf assays, the efficacy of the cry1Ia1 gene is retained through sexual transmission. If the SpuntaG2 cry1Ia1 insertion event is deregulated for commercial use, SpuntaG2 could be used for conventional breeding and the progeny carrying the SpuntaG2 event would also be available for commercial use.

Primary pulmonary tuberculosis in children remains a leading cause of mortality and morbidity in developing countries. Thirteen children requiring urgent thoracotomy for relief of acute respiratory distress resulting from critical major airway narrowing caused by enlarged tuberculous mediastinal lymph nodes were admitted to two hospitals over a 4-year period. Ages ranged from 2 months to 10 years. The condition of each patient had deteriorated despite appropriate antituberculosis therapy and an oral corticosteroid. At operation, the enlarged tuberculous subcarinal or paratracheal lymph nodes or both were decompressed. Surgical complications included a branchial tear and a pulmonary artery laceration. Additional procedures included a right upper lobectomy, two pneumonectomies, plication of a hemidiaphragm, and mobilization of two muscle flaps. Postoperatively all children showed dramatic improvement. The trachea to main bronchi diameter ratio improved by 49.1% on the left and 44.9% on the right in the immediate postoperative period. In children with respiratory distress produced by compression of the main bronchi between enlarged subcarinal and paratracheal lymph nodes, surgical decompression of the lymph nodes is indicated if there is no marked initial response to appropriate medical therapy. At operation, lymph nodes should be decompressed only by incision and curettage. Attempts at lymph node excision are associated with increased complications.

Application of the University of Wisconsin cold storage solution has rapidly expanded to include medium-term to long-term preservation of virtually all intraabdominal organs. Its use in intrathoracic organ transplantation has also been suggested. We therefore examined the efficacy of the University of Wisconsin solution in a primate allotransplantation model for preservation of hearts, and as a simple single-solution system for static preservation of heart-lung blocks, for periods of ischemia ranging from 6 to 24 hours. For comparison, we employed the histidine-tryptophane-ketoglutarate cardioplegic solution of Bretschneider. University of Wisconsin solution provided superior results with regard to clinical outcome and hemodynamic recovery of hearts after ischemic periods of up to 16 hours. This was in contrast to Bretschneider's solution, which allowed storage of hearts for periods of only up to 10 hours. Heart-lung blocks were equally well preserved with either University of Wisconsin or Bretschneider's solution after 6 to 12 hours, although the University of Wisconsin solution group exhibited a more notable increase in pulmonary water content. This was in accordance with histological data, which suggested that, although hemodynamic recovery of hearts stored for periods longer than 10 hours was poor, preservation of pulmonary ultrastructure was far superior using Bretschneider's solution as compared with University of Wisconsin solution after an ischemic period of up to 16 hours.

Part 1: Introduction 1. Knowledge Intensive Entrepreneurship and Innovation Systems in Europe Franco Malerba Part 2: Perspectives on Knowledge Intensive Entrepreneurship and Innovation Systems 2. The Knowledge-Based Entrepreneur: The Need for a Relevant Theory of the Firm Patrick Cohendet and Patrick Llerena 3. What Makes Entrepreneurship Systemic? Slavo Radosevic 4. Academic Patents, Spin-Offs and Beyond: The Many Faces of Scientific Entrepreneurship Chiara Franzoni and Francesco Lissoni Part 3: Knowledge Intensive Entrepreneurship and Innovation Systems: The European Case 5. Patterns of Technological Entry in Different Fields: an Analysis of Patent Data Roberto Camerani and Franco Malerba 6. Survival of Innovative Entrants in Knowledge Based Sectors Stefano Breschi, Franco Malerba and Maria Luisa Mancusi 7. Academic Inventors as Brokers: An Exploratory Analysis of the KEINS Database Francesco Lissoni 8. New Innovators and Knowledge Intensive Entrepreneurship in some European Sectoral Systems: A Field Camilla Lenzi, Kate Bishop, Stefano Breschi,Guido Buenstorf, Patrick Llerena, Franco Malerba, Maria Luisa Mancusi and Maureen McKelvey 9. Knowledge Intensive Entrepreneurship in Central and Eastern Europe: Results of a Firm Level Survey Slavo Radosevic, Maja Savic and Richard Woodward 10. Diversity of Knowledge-Intensive Entrepreneurial Firms: Struggling Biotech Firms Despite Opportunities Johan Brink and Maureen McKelvey 11. Knowledge-Based Entrepreneurship and International Technology Transfer in the German Laser Industry Guido Buenstorf 12. Are the Dynamics of Knowledge Intensive Industries any Different? Ricardo Mamede, Daniel Mota and Manuel Mira Godinho 13. Entrepreneurship and Growth David B. Audretsch and Max Keilbach Part 4: Policy Conclusions 14. Knowledge Intensive Entrepreneurship in Europe: Some Policy Conclusions Franco Malerba and Nicholas Vonortas

1. In many Coleoptera, iridescent colouration is generated by exoskeleton ultra-structure, within which multilayer interference reflects only certain wavelengths. Published work indicates that the colour polymorphism shown by some iridescent beetles is under genetic control. However, the present study suggests environmental involvement in the polymorphic southern African dung beetle, Gymnopleurus humanus Macleay. 2. At 24 study sites across a 1000-km latitudinal temperature gradient, population samples of G. humanus were dominated by blue individuals in the cooler south, by cupreous individuals in the warmer north, and by locally co-occurring blue, green and cupreous individuals in intermediate situations. 3. Using digital reflectance spectrophotometry, we measured wavelength intensity values across the visible spectrum (400–800 nm) and used the 70 measured specimens to estimate maximum reflectance from a further 3912 beetles. Differences in mean reflectance values between 24 populations were strongly correlated with average annual temperatures at study sites. 4. Much stronger correlations between mean reflectance values and average temperatures of the cool dry season months suggest that the cross-climatic patterns may be related to interaction between breeding seasonality and development under different cooler temperatures. 5. Published evidence suggests that inherent physical properties of cholesteric liquid crystals and their responses to different thermal conditions could, potentially, generate the different exocuticle ultra-structure responsible for different reflected colour wavelengths. Furthermore, colour polymorphism could be advantageous across a gradient from cooler to warmer climate as a result of the different thermal properties of different colours. 6. Given the correlation with temperature, it is predicted that the prevailing reflected colour balance in southern populations would shift in response to global climatic change.

This book offers a novel insight into the economic dynamics of modern biotechnology, using examples from Europe to reflect global trends. The authors apply theoretical insight to a fundamental enigma of the modern learning society, namely, how and why the development of knowledge and ideas interact with market processes and the formation of industries and firms.

This chapter addresses issues related to conceptualizing and measuring modern biotechnology, thereby raising questions of definitions, methodology and data. This chapter argues that behind many of the empirical and comparative issues lie fundamental problems of conceptualization of the empirical phenomena. Addressing these conceptual problems is important for analytical progress, but also for decision-makers in government policy, universities and firms.

This work proposes methodologies using a model-based approach to gain knowledge on and assist the development of an ion-exchange step in a protein purification process; the separation of IgG from a mixture containing IgG, insulin and transferrin. This approach is suitable for capture and intermediate steps in a process. Both methods involve four consecutive steps. Firstly, the retention of the different protein components is determined giving a retention map of the system. From this the optimal pH and buffer can be determined. Secondly, additional salt gradient experiments are performed at the selected pH. Thirdly, experimental breakthrough curves have to be generated for the protein if the adsorption capacity of the medium for each component is not known. Fourthly, a validation experiment is performed. In method 1, where the capacity for the medium is assumed to be known. the protein adsorption is described by Langmuir kinetics with a mobile phase modulator (MPM). In this description salt is considered to be inert. In method 2 the adsorption behavior is described by steric mass action (SMA), where the salt component competes with the proteins for the available binding sites. Both methods use a dispersion model to describe transport in the mobile phase in the column. The methods are able to predict the separation and loading behavior of the three components. The methods can, with reasonable accuracy, predict the breakthrough of transferrin in a mixture of insulin, IgG and transferrin. Method 1 requires fewer experiments and predicts the mean volume of breakthrough for the loading step in the validation experiment more accurately than method 2. On the other hand, method 2 has a better accuracy to predict the position of 10% breakthrough and the shape of the breakthrough curve. The methods suggested in this work are shown to be efficient in process development. Some additional experiments have to be performed to obtain the unknown parameters in the models. However, the predictability that is achieved results in less experimental work in the process design as a whole.

We investigated the dynamics of the CD4+ and CD8+ lymphocyte subsets, and the expression of activation markers in cardiac transplant recipients. We tested 132 peripheral blood samples from 62 cardiac transplant recipients using fluorescent staining and flow cytometry analysis. The results were correlated with histological rejection grade of concurrently taken biopsies, and 5-year survival of the recipients. A decrease in the total T lymphocyte subset, and in CD4+ lymphocytes was associated with higher rejection grade and lesser survival. An increase (5-11%) of double positive CD4+ CD8+ lymphocytes was observed; these were mostly CD4brightCD8dim. The CD4/CD8 ratio was significantly (P < 0.00) lower in the transplant recipients than in normal individuals. CD69 expression was higher than CD54 and CD154 expression on CD4 and CD8 lymphocytes of cardiac transplant recipients; correlation between these activation markers was excellent (P < 0.001). Fluorescent staining for CD69 was often of low intensity. Multiple regression for % CD8+ CD69+ cells and survival, and for % CD69+ T cells and rejection grade yielded a significant correlation (P < 0.050). Both % CD8+ CD69+ and % CD69+ T cells were significantly higher in samples with severe and moderate rejection grade (grades 3A, 3B and 4) than in samples which showed no, minimal or mild rejection (grades < or = 2); P-values were 0.052 and 0.003, respectively. Preliminary results indicated that false negative results could be contributed to increased immunosuppression. We conclude that CD69 expression on circulating CD4 and CD8 lymphocytes is a useful parameter for the diagnosis of moderate and severe rejection.

Background It is not known whether strict control of blood pressure (BP) in mild post-transplant hypertension gives any benefit. Our primary objective was to test the antihypertensive effects of lisinopril added to standard therapy on ambulatory BP (ABP) of post-transplant patients. The secondary objective was to monitor echocardiographic and hemodynamic end points. Methods Post-transplant patients with an abnormality of the 24-h ABP recording were recruited to this double-blind randomized prospective study that started 2 to 3 months after transplantation. Patients were then evaluated at 6, 12, 18, and 24 months after transplantation. Results: Lisinopril decreased the clinic BP and ABP, the latter from 134/85 to 126/82 mm Hg at 6 months ( P = .01 v placebo) and 121/79 mm Hg after 2 years ( P = .03 v placebo). Fewer patients in the lisinopril group required added amlodipine to control the BP ( P = .01). Data on left ventricular (LV) mass are difficult to interpret because by coincidence in this small study, the lisinopril group had lower initial values than placebo. However, in the lisinopril group mean LV mass decreased by 10% ( P = .02) and mass index by 13% ( P = .01), whereas placebo LV mass and index did not change. The LV end-diastolic diameter increased only in the placebo group ( P = .008). There were no significant changes in any of the other secondary outcomes, including the cardiac index and systemic vascular resistance. Conclusions Thus, in these post-transplant patients, stricter BP control to normal levels by the addition of lisinopril to existing therapy, reduced BP and modestly decreased LV mass without altering cardiac hemodynamic function.

The chemical glue, gelatin, resorcin and formaldehyde (GRF) is widely used to obliterate the false lumen of acute dissected aortic wall tissue.A retrospective review of 41 consecutive patients operated upon for ascending aortic dissection between 1993 and 2000 was conducted. This study focused on 19 patients with acute aortic dissection in whom the aortic valve was resuspended and GRF glue used in the proximal aortic sinuses. These patients were compared with ascending aortic dissection patients in whom the aortic valve was not resuspended. In total, nine acute and 13 chronic dissections were performed in which aortic valve replacement, valve-sparing root reconstruction (without GRF glue), or no aortic valve surgery was carried out.The operative mortality for ascending aortic dissections was 24.4%; identified risk factors included the specific surgeon involved. Third-degree heart block occurred only in patients in whom GRF glue was used in the proximal aortic sinus (15% incidence). Operative survivors in whom the aortic valve was resuspended and GRF glue used in the proximal aortic sinus, had a 64% incidence of late recurrent aortic regurgitation requiring reoperation due to recurrent aortic sinus aneurysm formation with or without recurrent proximal aortic dissection. No recurrence of aortic regurgitation or proximal disease occurred in the other two groups (p0.01). Actuarial survival of patients in whom the aortic valve was resuspended with GRF glue was 52.1+/-11.6% at five years and 27.8+/-14.3% at eight years, compared with 55.6+/-16.6% at five years if the aortic valve was not resuspended using GRF glue.The use of GRF glue to repair acute dissected aortic sinuses combined with the resuspension of the aortic valve is associated with an unacceptable incidence of failure of aortic valve repair and recurrence of aortic regurgitation. It may be more appropriate to resect all acute dissected aortic sinus tissue.

A case of angiographically occult traumatic aorto-caval fistula masquerading as aorto-right atrial fistula is presented. The importance of angiographic vigilance in the imaging of arterio-venous fistula is emphasized.

Objecti6e: Pulmonary artery banding remains a palliative option for patients with congenital heart disease and excessive pulmonary blood flow, if there is unfavourable anatomy or frail condition. In contrast to more developed countries, our patients at Red Cross Children’s Hospital, Cape Town, often present to medical services late and in poor nutritional condition. We retrospectively reviewed patients undergoing pulmonary artery banding to determine major variables that influenced long-term outcome. Methods: In a 10-year period ending June 1992, 135 consecutive patients underwent pulmonary artery banding; 89 with ventricular septal defect type non-mixing disorders, and 46 with mixing or complex disorders. The median age was 3.0 months and weight 3.5 kg with 74.8% of patients weighing less than the third percentile (NCHS adapted), and 39.3% had an additional serious medical illness. Results: Pulmonary banding mortality was 8.1%, and was higher in neonates (22.2%, P 0.04) but was not related to congenital disorder, associated medical illness, or associated coarctation or interrupted aortic arch. The pulmonary band was inadequate at follow-up in 28.9%, which occurred more commonly if banding was necessary before 3 months of age (41.5%, P0.003) but was not related to weight, congenital disorder or associated respiratory infection. Sixty patients (44.4%) have now proceeded to definitive repair with a mortality of 23.3%, which was increased if the pulmonary band was inadequate at the time of definitive repair (44.4%; P0.02), but was not related to the congenital disorder. Conclusions: An inadequate pulmonary artery band adversely affects outcome and demands further aggressive management prior to definitive repair. Copyright © 1997 Elsevier Science B.V.

Background: Threshold countries like South Africa provide cardiac surgery to a largely indigent population with rheumatic heart disease. Although repairs are a preferred treatment modality many rheumatic mitral valves can only be replaced. In view of significantly improved primary health care and broad access of the indigent population to communication technology we revisited the efficacy of mitral valve replacement (MVR) at the interface of the developing and developed world. Methods: A cohort of 280 patients (mean age 40.7±13.7y/range 12-80y/median 41y; 76.4% female) with rheumatic heart disease (21% MR; 11% MS; 68% mixed) undergoing mitral valve replacement (MVR) (88.2% mechanical versus 11.8% tissue valves) was analyzed.

Gelatin-resorcin-formaldehyde-glutaraldehyde (GRF) biologic glue is an available adjunct to repair acute ascending aortic dissections. Permanent complete heart block complicated the operative repair of 2 of 6 patients. The pathophysiology of heart block resulting from either the acute dissecting process or the technique of applying GRF glue is discussed.

This report describes the findings and management of a young male who presented with an acute ST-segment elevation myocardial infarction due to compression of the circumflex coronary artery by a large aneurysm of left sinus of Valsalva.

To the Editor: Tuberculosis (TB) remains a major threat to health in developing countries and in HIV-1–infected persons (1). In sub-Saharan Africa, the most common etiology of pericardial effusions in HIV-1–infected persons is TB (2). Mortality in patients with tuberculous pericarditis coinfected with HIV-1 can reach 40% in the absence of antiretroviral treatment, and neither antimicrobial therapy of TB alone nor the addition of corticosteroids to chemotherapy resulted in a clinically satisfactory mortality reduction, although corticosteroids significantly reduced hospitalization and incidence of constrictive pericarditis, regardless of HIV status (3). Improved understanding of immunological mechanisms at the disease site is required for the development of more effective host-directed therapies. Because HIV-1 coinfection alters the memory phenotype of CD4+ T cells in the pericardium (4), we hypothesized that HIV infection would also affect transcript abundance of key immune mediators in pericardial TB at the disease site. Based on known transcriptional perturbation in extrapulmonary TB (5–9), we selected 42 analytes and performed differential transcriptomic analysis by quantitative reverse transcription polymerase chain reaction in paired blood and pericardial fluid from 27 patients (15 definite and 12 probable patients with tuberculous pericarditis, and 17 patients coinfected with HIV-1). We report a detailed immunopathological characterization of pericardial TB, with 21 analytes also confirmed at the protein level. Methods, patient characteristics (see Tables E1 and E2 in the online supplement), and raw data for all genes in blood and pericardial fluid (Tables E3 and E4) are detailed in the online supplement. Preliminary data have been reported in the form of an abstract (10). A rigorous data analysis was conducted (Figure 1A). Briefly, pairwise fluid versus blood comparisons of individual genes yielded 21 differentially expressed genes in pericardial fluid compared with blood after application of Benjamini-Hochberg multiple testing correction (Tables E4). Next, cluster analysis was employed, with the resulting heat map (Figure E1) showing that strikingly, most blood and pericardial fluid samples from individual patients clustered together. This appeared to be driven by highly correlated gene expression patterns between the two compartments, as further shown in the correlation matrices of blood and pericardial fluid samples (Figure E2). Gene coexpression patterns in blood differed from pericardial fluid, in which pronounced coexpression of fibrosis-associated and neutrophil-associated genes were evident, as well as coexpression of some pro- and anti-inflammatory genes. Given the very low levels of transcript for some genes, a nonspecific filter was applied, which removed transcripts with a delta cycle threshold value higher than 38 in 5% or more of the samples. This step left 22 genes that separated blood and pericardial fluid, with five samples not assigned to either of the main blood or pericardial fluid clusters (Figure E3). This result indicates that overall gene expression in the two compartments is very different and confirmed our previous impression that genes with low levels of expression drive the patient-specific clustering. Figure 1. (A) Outline showing the flow of data in the analytic pipeline. (B) Clustered heat map of 17 selected genes, showing blood and pericardial fluid samples grouped into two separate compartments with prominence of fibrosis-associated genes in pericardial ... Next, computation of differential transcript abundance with multiple testing correction using a linear models approach identified 17 transcripts to be differentially abundant between the blood and pericardial fluid compartments (Table 1), which collectively clustered the samples into two separate compartments of blood and pericardial fluid (Figure 1B). A correlation matrix of the 17 selected genes pointed to the prominent coexpression of fibrosis-associated genes in pericardial fluid (Figure E4). Principal component analysis of the data using the three gene sets (“all genes,” showing no differential gene expression between the compartments; 22 “filtered genes,” which indicated a difference between the two compartments; and 17 “selected genes”) showed that the first principal component of the 17 differentially expressed genes explained 60% of the observed variance (Figure E5). Table 1. Differential Abundance of Gene Products by Disease Site, as Measured by Either Reverse Transcription Polymerase Chain Reaction (RNA) or ELISA/Luminex (Protein) To assess whether differential transcript abundance between blood and pericardial fluid was modulated by factors that plausibly reflect differential immune status or modulation thereof, we implemented an analysis in limma (Linear Models for Microarray Data), based on a factorial design, in which we compared the transcript abundance levels between compartments, taking into account the following interaction terms: HIV-1 coinfection status, CD4 count below 200 cells/μl, concurrent corticosteroid use, and pericardial fluid Mycobacterium tuberculosis culture result. None of these factors had a significant effect on differential transcript abundance (Figure 1B and Figure E6). The immunophenotype of the host response at the disease site was next assessed at the protein level (Table E4); results of fold changes between compartments are summarized in Table 1. In general, protein levels and patterns of over- or underabundance mirrored those of mRNA transcripts. Two exceptions were IFN-γ and IL-1β, both of which were significantly more abundant as proteins in pericardial fluid, but the corresponding mRNA transcript abundance was either no different or significantly lower than in blood (Table 1). We hypothesized that the difference could be a result of antigen-specific T cells that enter the pericardium, release IFN-γ, and die, potentially activating the inflammasome pathway, resulting in pyroptosis and release of IL-1β protein (11). Therefore, we assessed cell death in the pericardial compartment by comparing the cell death enrichment factors in pericardial fluid from cases of tuberculous pericarditis (n = 24) and those from asymptomatic controls undergoing cardiac surgery (n = 28) and found that cell death significantly increased in tuberculous pericarditis cases (P = 2.4 × 10−7) compared with controls (Figure E7), with no difference observed between HIV-infected and uninfected samples. In summary, we report a strong profibrotic response of gene expression in pericardial fluid, with a differentially stronger pro-inflammatory response also confirmed at the protein level. We show a transcriptomic gene expression signature of 17 genes that differentiate blood from pericardial fluid in patients with pericardial TB, and these transcripts were associated with fibrosis and regulators of fibrosis, as well as matrix metalloproteinases and tissue inhibitors of metalloproteinases. Also, unexpectedly and contrary to the effect on T-cell phenotype, HIV-1 infection does not affect the expression profile of key immune mediators at the pericardial TB disease site. Although we recognize the bias and the limitation introduced by the selection of 42 very specific genes, our data serve to justify a full transcriptional analysis at the microarray level. Further studies including more patients and an unbiased selection of genes will provide more detailed insight into molecular mechanisms and immunopathology during TB infection of the pericardium, and thereby lead to improved host-directed therapy. Future therapeutic approaches could target regulators of fibrosis and apoptosis, with the aim of preventing fibrosis, morbidity, and mortality.

This book offers a novel insight into the economic dynamics of modern biotechnology, using examples from Europe to reflect global trends. The authors apply theoretical insight to a fundamental enigma of the modern learning society, namely, how and why the development of knowledge and ideas interact with market processes and the formation of industries and firms.

This book offers a novel insight into the economic dynamics of modern biotechnology, using examples from Europe to reflect global trends. The authors apply theoretical insight to a fundamental enigma of the modern learning society, namely, how and why the development of knowledge and ideas interact with market processes and the formation of industries and firms.