[Show abstract][Hide abstract] ABSTRACT: This study aimed to systematically evaluate safety of probiotics and synbiotics in immune compromised adults (≥18 years). Safety was analysed using the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification, thereby providing an update on previous reports using the most recent available clinical data (2008- 2013). Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 57 clinical studies indicates that probiotic and/or synbiotic administration in immune compromised adults is safe with regard to the current evaluated probiotic strains, dosages and duration. Individuals were considered immune compromised if HIV-infected, critically ill, underwent surgery or had an organ- or an autoimmune disease. There were no major safety concerns in the study, as none of the serious adverse events (AE)s were related, or suspected to be related, to the probiotic or synbiotic product and the study products were well tolerated. Overall, AEs occurred less frequent in immune compromised subjects receiving probiotics and/or synbiotics compared to the control group. In addition, the results demonstrated a flaw in precise reporting and classification of AE in most studies. Furthermore, generalisability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes. We argue that standardised reporting on adverse events (CTCAE) in 'food' studies should be obligatory, thereby improving reliability of data and re-enforcing the safety profile of probiotics.
[Show abstract][Hide abstract] ABSTRACT: A plethora of terms and definitions for medical nutrition has resulted in an ambiguity in the way “medical nutrition” is termed and defined across various societal levels. The terms medical nutrition, clinical nutrition, enteral nutrition, parenteral nutrition, oral nutritional supplements, medical foods, foods for special medical purposes, nutritional support, nutritional intervention and nutritional therapy are used interchangeably. To date consistent terminology/nomenclature and definitions have not emerged from the US and European medical nutrition community. The current absence of clear medical nutrition product category boundaries makes it necessary to introduce medical nutrition terminology conformance in order to reduce widespread confusion at policy; industry; healthcare; and patient level. In order to end discussion, this literature review attempts to put quantitative and qualitative clarity and continuity to the use of these terms and definitions by: (1) addressing the terminology used; (2) discussing the distinguishing features of medical nutrition in various definitions and (3) proposing a single medical nutrition term and a clear pragmatic operational definition. A scientific literature-based comparison was conducted resulting in the selection of 22 publications, describing 8 different terms with 19 definitions.
Based on the terminology found in literature, the following medical nutrition terminology is proposed: medical nutrition comprises both parenteral (intravenous) as well as enteral nutrition (tube feeding and oral nutrition), which may be given via the oral route or via a tube into the gastrointestinal tract. The features found to be most important in describing medical nutrition are: route of administration; disease; supervision; composition and support/management. These features have been integrated into one operational clinical definition and resulted in the following definition: MEDICAL NUTRITION: specially formulated nutritional composition for the dietary management of patients with diseases, disorders or medical conditions that cause distinct nutritional requirements. It may consist of partial or exclusive feeding by means of oral intake, tube feeding and/or parenteral administration under healthcare professional supervision.
[Show abstract][Hide abstract] ABSTRACT: This exploratory qualitative article analyzes the potentially rate-limiting factors affecting value chain dynamics during adjuvanted-vaccine development. Adjuvants are considered immunostimulating substances that can be added to a vaccine. Although adjuvants have the potential to elicit adverse reactions, they also offer certain benefits. After approximately 90 years of R&D, why have only four adjuvants been approved? Although ample literature is available describing the risks and benefits, it remains unclear as to how these potentially rate-limiting factors compare.
Experts – representing knowledge institutes, industry and regulatory/public health authorities – were approached in order to collect a unique weighted-ranking dataset on rate limiting factors. Based on the principal–agent theory, there is a partial conflict of interests between the internal perceptions on the challenges faced. Additionally, content analysis reveals four underlying social constructs influencing this perception, namely: attitudes towards risk management, innovation strategy, valuation and funding.
This study was designed to explore the topic of rate-limiting factors, and not intended to solve the issues. Moreover we offer previously unpublished and practical insights on the topic, and offer a validated starting point for further research. Ultimately, we would advocate more transparency on reasons for project discontinuation; sharing lessons learned from failed attempts could prove valuable for advancing the field of virosciences.
Technological Forecasting and Social Change 05/2014; · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we systematically evaluated safety aspects in clinical trials with probiotics and synbiotics in young infants (0-2 years of age). This study is an update of earlier reports and covers the recent literature from 2008-2013. The safety evaluation is performed along the Common Terminology Clinical Adverse Events (CTCAE) version 4.0 scale, hereby also providing guidance for future studies. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. The results show a deficiency in the precise reporting and classification of adverse events in most studies. Analysis of 57 clinical trials with probiotics and synbiotics in combination with eight follow-up studies indicate that probiotic administration to infants between 0 and 24 months is safe with regard to the evaluated strains in infants with a particular health status or susceptibility. Most adverse events and serious adverse events were considered unrelated to the study product, and there were no major safety concerns. Almost all studies concluded that none of the adverse effects were related to the study product; the study products are generally well tolerated. Finally, inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes, greatly limit the generalizability of conclusions and argue convincingly for obligatory and standardised behaviour on adverse events (CTCAE) reporting in 'food' studies.
[Show abstract][Hide abstract] ABSTRACT: A quantitative systematic identification and prioritization of unmet needs and research opportunities in relation to enteral nutrition was conducted by means of a tailor-made health research prioritization process.
The research objectives were reached by conducting qualitative interviews followed by quantitative questionnaires targeting enteral nutrition key opinion leaders (KOLs). (1) Define disease areas that deserve more research attention; (2) Rank importance of product characteristics of tube feeding (TF) and oral nutritional supplements (ONS); (3) Assess involvement of KOLs in enteral nutrition R&D process. KOLs ranked three product characteristics and three disease areas that deserve additional research attention. From these, overall priority scores were calculated by multiplying ranks for both product characteristics and disease areas.
17 qualitative interviews were conducted and 77 questionnaires (response rate 35%) were completed and returned. (1) Disease areas in ONS and TF with highest priorities are: ONS: general malnutrition & geriatrics, TF: intensive care. (2) TF product characteristics with highest priorities are: composition and clinical evidence from a KOL perspective; tolerance and ease of use from a patient perspective. ONS product characteristics with highest priorities are: composition, clinical evidence and taste from a KOL perspective; taste from a patient perspective. We find a high discrepancy between product characteristic prioritization from a KOL and patient perspective. (3) Although 62% of all KOLs give advice to enteral nutrition companies on patient needs, they under-influence the setting of research priorities by enteral nutrition companies.
This study provides a systematic approach to achieve research prioritization in enteral nutrition. In addition to providing new directions for enteral nutrition research and development, this study highlights the relevance of involving KOLs in the identification of research priorities as they have the ability to provide a balanced view of the unmet patient needs.
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggested that manipulation of the composition of the microbial ecosystem in the gut might be a novel approach in the treatment of obesity. Such treatment might consist of altering the composition of the microbial communities of an obese individual by administration of beneficial microorganisms, commonly known as probiotics. Here, we intend to contribute to the developmental process of probiotic treatment of human obesity. The aim is to review the evidence regarding the potential effect of probiotic strains on reduction of weight and body fat. A literature study was conducted focusing on clinical trials that examined the effect of specific microorganisms on body weight control. Analysis of the eligible articles pointed out that Lactobacillus gasseri SBT 2055, Lactobacillus rhamnosus ATCC 53103, and the combination of L. rhamnosus ATCC 53102 and Bifidobacterium lactis Bb12 may reduce adiposity, body weight, and weight gain. This suggests that these microbial strains can be applied in the treatment of obesity. Furthermore, short chain fatty acid production and low grade inflammation were found as the underlying mechanisms of action that influence metabolism and affect body weight. These findings might contribute to the development of probiotic treatment of obesity. Further research should be directed to the most effective combination and dosage rate of probiotic microorganisms.
[Show abstract][Hide abstract] ABSTRACT: During the past two decades the biopharmaceutical industry has been facing an innovation deficit, characterized by in- creasing research & development costs and stagnant productivity. From its inception, biotechnology has been expected to counter this deficit by its revolutionary science-based approach to drug discovery. For this study we gathered patent and product data related to the technological development of the first two biotechnologies: recombinant DNA technol- ogy and monoclonal antibody technology. We studied the technological lifecycles of these technologies in terms of sci- entific discoveries and inventions as well as product innovations. Results indicate that over the years inventions related to these technologies have simultaneously become less radical and less valuable. Furthermore, our analysis shows that these biotechnologies have reached a stage of technological limit or saturation, which may be followed by an innovation cliff. Now, more than ever, it is crucial to examine new strategies and opportunities for value creation, capturing, and delivery, within the biopharmaceutical industry.
Technology and Investment 07/2013; 43020(4):168-178.
[Show abstract][Hide abstract] ABSTRACT: Innovation is a necessity for survival in dynamic and complex industries such as the medical nutrition industry. To remain competitive, medical nutrition companies must embrace innovation activities that improve productivity. Nevertheless, innovation is a difficult undertaking and companies must first overcome numerous barriers inhibiting innovation. Studying these barriers provides insight into the dynamics of innovation, which simultaneously is a first step in the process of overcoming them. This study investigates the exogenous barriers that inhibit medical nutrition innovation.Primary data was collected by qualitative interviews from 17 medical nutrition key opinion leaders (KOLs) through and quantitative data by means of a questionnaire from 77 KOLs. Medical nutrition innovation barriers were identified and ranked according to importance.This study shows that barriers impact all steps of the medical nutrition value chain. Nine main innovation barriers emerged from the research. The most significant barriers are associated with financial aspects and clinical research, whereas the least significant are associated with product barriers. Medical nutrition companies must realize that investment in innovation is and remains crucial within this industry.
[Show abstract][Hide abstract] ABSTRACT: At present, industries within the health and life science sector are moving towards one another resulting in new industries such as the medical nutrition industry. Medical nutrition products are specific nutritional compositions for intervention in disease progression and symptom alleviation. Industry convergence, described as the blurring of boundaries between industries, plays a crucial role in the shaping of new markets and industries. Assuming that the medical nutrition industry has emerged from the convergence between the food and pharma industries, it is crucial to research how and which distinct industry domains have contributed to establish this relatively new industry. The first two stages of industry convergence (knowledge diffusion and consolidation) are measured by means of patent analysis. First, the extent of knowledge diffusion within the medical nutrition industry is graphed in a patent citation interrelations network. Subsequently the consolidation based on technological convergence is determined by means of patent co-classification. Furthermore, the medical nutrition core domain and technology interrelations are measured by means of a cross impact analysis. This study proves that the medical nutrition industry is a result of food and pharma convergence. It is therefore crucial for medical nutrition companies to effectively monitor technological developments within as well as across industry boundaries. This study further reveals that although the medical nutrition industry's core technology domain is food, technological development is mainly driven by pharmaceutical/pharmacological technologies Additionally, the results indicate that the industry has surpassed the knowledge diffusion stage of convergence, and is currently in the consolidation phase of industry convergence. Nevertheless, while the medical nutrition can be classified as an industry in an advanced phase of convergence, one cannot predict that the pharma and food industry segments will completely converge or whether the medical industry will become an individual successful industry.
PLoS ONE 01/2013; 8(12):e82609. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medical nutrition products are specific nutritional compositions for intervention in disease progression and symptom alleviation. This industry finds itself on the interface between the food and pharmaceutical industry and is still a relatively unknown industry. At present, insights concerning industry development and patenting in the European medical nutrition industry are limited. This research presents a systematic patent portfolio analysis of the industrial patenting trends and patenting strategy categorization of the 5 leading companies.Focusing on EU patent applications, we calculated company specific patent-, product- and market shares and average forward- and backward-citations. These indicators were combined to illustrate the European medical nutrition industry trends and company specific patent- and innovation-strategies. We found 222 European medical nutrition patent applications between 1990 and 2010.The analysis of the industry trends shows that the industry currently resides in the growth phase and is estimated to reach the stage of maturation within 2 years with approximately 400 patents. Predominantly neurological diseases, cancer and diabetes show opportunity for future MN innovations while gastrointestinal and infection related diseases may have already reached a market saturation stage. Three distinct patent strategies can be distinguished within this industry: the Prospector; the Analyzer; and the Reactor.
[Show abstract][Hide abstract] ABSTRACT: As infectious diseases cause approximately 25% of the annual global mortality, vaccines are found to be a time proven and promising response to infectious disease need. However, like for pharmaceutical small molecules, vaccine development is lengthy, risky and resource demanding. Faced with an attrition rate estimated around 80%, key opinion leaders were interviewed with the question: is there a recipe for success?
[Show abstract][Hide abstract] ABSTRACT: In this study we present new data showing strain-specific differences on the effect of commercially available probiotic drinks in an EAE rat autoimmune model for multiple sclerosis. In this particular model, we conclude that these drinks do not enhance but rather suppress the disease. We suggest that conclusions on probiotics are limited to specific strains and models and not generalised. We further suggest that physiological use (normal route, normal dose, normal growth phase, specific strain or substrain/species) is studied in all cases, so as not to overwhelm (high dose) or circumvent natural immune processing.
[Show abstract][Hide abstract] ABSTRACT: Recent data suggest that the spleen is a crucial component of the immune system in the development of experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys. Using immunohistochemistry, we investigated changes in the distribution of leukocytes in the spleen associated with clinical symptoms of EAE. Animals without EAE displayed well-developed T- and B-cell areas, germinal centers and red pulp. In contrast, a marked depletion of periarteriolar T cells with preservation of other elements was found in animals with clinical EAE. These findings suggest that immune responses within the spleen are impaired during a paralysing inflammatory process in the central nervous system.
Journal of Neuroimmunology 05/2005; 161(1-2):29-39. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ectromelia virus (ECTV), a natural mouse pathogen and an orthopoxvirus, has been used to investigate the correlation between polarized type 1 or type 2 immune responses and resistance to disease in poxvirus infections by using well defined resistant and susceptible mouse strains. Our data show that distinct differences exist in the cytokine profiles expressed in resistant and susceptible mice infected with ECTV. Resistant C57BL/6 mice generate a type 1 cytokine response [IFN-gamma, IL-2, and tumor necrosis factor (TNF)], within the first few days of infection, which is associated with strong cytotoxic T lymphocyte response (CTL) and recovery from ECTV infection. Susceptible strains of mice (BALB/c and A/J) on the other hand generate a type 2 cytokine response (IL-4 but little or no IFN-gamma and IL-2), which is associated with a weak or an absent CTL response, resulting in uncontrolled virus replication and death. Although deletion of IL-4 function alone did not change the outcome of infection in susceptible mice, the loss of IFN-gamma function in resistant mice abrogated natural killer (NK) cell and CTL effector functions resulting in fulminant disease and 100% mortality. Therefore, a clear link exists between the early production of specific type 1 cytokines, in particular, IFN-gamma, the nature of the cellular immune response, and disease outcome in this virus model. This finding in the mousepox model raises the possibility that inappropriate cytokine responses may result in increased susceptibility to smallpox in humans.
Proceedings of the National Academy of Sciences 07/2004; 101(24):9057-62. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use genetically modified lactobacilli expressing myelin antigens. A panel of recombinant lactobacilli was constructed producing myelin proteins and peptides, including human and guinea pig myelin basic protein (MBP) and proteolipid protein peptide 139-151 (PLP(139-151)). In this study we examined whether these Lactobacillus recombinants are able to induce oral and intranasal tolerance in an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Lewis rats received soluble cell extracts of Lactobacillus transformants intranasally three times prior to induction of EAE. For the induction of oral tolerance, rats were fed live transformed lactobacilli for 20 days. Ten days after the first oral administration EAE was induced. Intranasal administration of extracts containing guinea pig MBP (gpMBP) or MBP(72-85) significantly inhibited EAE in Lewis rats. Extracts of control transformants did not reduce EAE. Live lactobacilli expressing guinea pig MBP(72-85) fused to the marker enzyme beta-glucuronidase (beta-gluc) were also able to significantly reduce disease when administered orally. In conclusion, these experiments provide proof of principle that lactobacilli expressing myelin antigens reduce EAE after mucosal (intranasal and oral) administration. This novel method of mucosal tolerance induction by mucosal administration of recombinant lactobacilli expressing relevant autoantigens could find applications in autoimmune disease in general, such as multiple sclerosis, rheumatoid arthritis and uveitis.
[Show abstract][Hide abstract] ABSTRACT: Using a novel multilocus DNA marker analysis method, we studied the population genetic structure of Trypansoma brucei stocks and derived clones isolated from animal and rhodesiense sleeping sickness patients during a national sleeping sickness control program in Mukono district, Uganda. We then performed a cladistic analysis to trace relationships and evolution, using stocks and clones recovered from geographically and temporally matched hosts, including inter-strain comparisons with T. b. gambiense stocks and clones. Our results show that while there was close genetic relatedness among parasite populations from the same geographical region, micro-heterogeneities exist between different stocks. Data are presented that indicate that not every human sleeping sickness focus may be associated with a particular human-infective trypanosome strain responsible for long-term stability of the reference focus. We provide evidence of genetic sub-structuring among type 1 T. b. gambiense stocks, which has potentially important implications for molecular epidemiology of T. brucei.
Infection Genetics and Evolution 10/2003; 3(3):165-74. · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There have been tremendous advances in our knowledge of trypanosome biology, yet many aspects remain unclear. Currently, the genome of Trypanosome brucei is being sequenced and this, with other genome-wide analysis methods, could provide novel insights into the parasite and facilitate the development of effective controls. An important new challenge investigators face is how to exploit the information in studying a parasite with so many genetic peculiarities. Here, we summarize our current understanding of molecular genetics of T. brucei and attempt to link genome analysis to the prospects for identifying possible targets for vaccines, novel drugs and specific diagnostics. The value of newly developed genotyping approaches in accelerating these processes is discussed.
Trends in Microbiology 08/2003; 11(7):322-9. · 8.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lactobacillus strains with probiotic activity are major constituents of numerous common food products. Due to their 'generally regarded as safe'-status (GRAS-status), Lactobacillus strains can also be genetically engineered for use in oral immunotherapeutic applications, such as vaccination and T lymphocyte tolerance induction in autoimmune disease.In the current study, we demonstrate that the growth phase of orally administered individual Lactobacillus strains can differentially affect antigen-specific antibody subclasses IgG1 and IgG2a, which might reflect skewing of systemic activity of T helper cell type 2 (Th2) and T helper cell type 1 (Th1) pathways, respectively. Mice were orally fed different wild type Lactobacillus strains in log phase or stationary phase and immunized intraperitoneally with a T-cell dependent protein antigen. Sera were evaluated for the ratio of antigen-specific IgG1 and IgG2a antibodies. Stationary Lactobacillus murines and Lactobacillus casei cultures, but not two other Lactobacillus strains, evoked significantly higher IgG1/IgG2a ratios than log phase cultures, possibly relating to increased activity of the Th2-pathway. Despite normal variation in antibody responses against TNP-CGG among individual mice, a high correlation was found between the IgG1 and IgG2a responses of mice within experimental groups. This differential antibody response is likely due to growth phase-dependent differences in bacterial cell composition.Since Lactobacillus growth phase dependent skewing of antibody responses possibly reflecting T-cell pathways can inadvertently affect allergic and (auto)-immune responses, the current findings strongly caution against unidimensional views on the oral administration of individual Lactobacillus strains for probiotic or immunotherapeutic purposes, but also suggest additional possibilities for immune modulation.
[Show abstract][Hide abstract] ABSTRACT: The pathogenic trypanosomes Trypanosoma equiperdum, T. evansi as well as T. brucei are morphologically identical. In horses, these parasites are considered to cause respectively dourine, surra and nagana. Previous molecular attempts to differentiate these species were not successful for T. evansi and T. equiperdum; only T. b. brucei could be differentiated to a certain extent. In this study we analysed 10 T. equiperdum, 8 T. evansi and 4 T. b. brucei using Random Amplified Polymorphic DNA (RAPD) and multiplex-endonuclease fingerprinting, a modified AFLP technique. The results obtained confirm the homogeneity of the T. evansi group tested. The T. b. brucei clustered out in a heterogenous group. For T. equiperdum the situation is more complex: 8 out of 10 T. equiperdum clustered together with the T. evansi group, while 2 T. equiperdum strains were more related to T. b. brucei. Hence, 2 hypotheses can be formulated: (1) only 2 T. equiperdum strains are genuine T. equiperdum causing dourine; all other T. equiperdum strains actually are T. evansi causing surra or (2) T. equiperdum does not exist at all. In that case, the different clinical outcome of horse infections with T. evansi or T. b. brucei is primarily related to the host immune response.