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An expert panel was convened in September 2019 by The International Scientific Association for Probiotics and Prebiotics (ISAPP) to develop a definition for fermented foods and to describe their role in the human diet. Although these foods have been consumed for thousands of years, they are receiving increased attention among biologists, nutritionists, technologists, clinicians and consumers. Despite this interest, inconsistencies related to the use of the term ‘fermented’ led the panel to define fermented foods and beverages as “foods made through desired microbial growth and enzymatic conversions of food components”. This definition, encompassing the many varieties of fermented foods, is intended to clarify what is (and is not) a fermented food. The distinction between fermented foods and probiotics is further clarified. The panel also addressed the current state of knowledge on the safety, risks and health benefits, including an assessment of the nutritional attributes and a mechanistic rationale for how fermented foods could improve gastrointestinal and general health. The latest advancements in our understanding of the microbial ecology and systems biology of these foods were discussed. Finally, the panel reviewed how fermented foods are regulated and discussed efforts to include them as a separate category in national dietary guidelines., Although fermented foods have been consumed for thousands of years, a clear definition has been lacking. This Consensus Statement outlines a definition for the term ‘fermented foods’ as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in September 2019.

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Purpose To evaluate the technical success of percutaneous retrograde revascularization of the superior mesenteric artery (SMA) via the celiac artery (CA) in patients with chronic mesenteric ischemia (CMI). Methods We performed a retrospective review of three patients with chronic total occlusions (CTOs) of the origin of SMA which were recanalized retrograde via collaterals of the CA after frustrating attempt of antegrade revascularization from the abdominal aorta in our institute between May 2019 and June 2020. Results All technical procedures of retrograde revascularization of CTOs of SMA via collaterals of the CA were successful. The clinical outcome resulted in a sustained resolution of abdominal pain in all cases. Conclusion Retrograde recanalization of SMA via collaterals from the CA seems to be a successful endovascular option for patients with CMI and a chronically occluded superior mesenteric artery when antegrade recanalization fails as far as it can be concluded from the small number of presented cases.

The gut microbiome is considered as a promising target for future non-conventional therapeutic treatment of inflammatory and infectious diseases. The search for appropriate safe and beneficial (lactic acid bacterial and other) putative probiotic strains and/or their antimicrobial metabolites represents a challenging approach for combating several problematic and emerging infections. The process of selecting suitable strains, especially of lactic acid bacteria (LAB) with superior properties, has been accelerated and intensified during the past two decades, also thanks to recent developments in lab techniques. Currently, special focus is on the potential of antimicrobial metabolites produced by some LAB strains and their application as active therapeutic agents. The vision is to develop a scientific basis for ‘biotherapeutics’ as alternative to conventional approaches in both human and veterinary medicine. Consequently, innovative and promising applications of LAB to the therapeutic practice are presently emerging. An overview of the existing literature indicates that some antimicrobial metabolites such as bacteriocins, widely produced by different bacterial species including LAB, are promising biotherapeutic agents for controlling infections caused by potential pathogens, such as Clostridium and Clostridiodes. Non-conventional, safe and well designed therapeutic treatments may contribute to the improvement of gut dysbiotic conditions. Thereby gut homeostasis can be restored and inflammatory conditions such as gastrointestinal colitis ameliorated. Combining the knowledge on the production, characterization and application of bacteriocins from probiotic LAB, together with their antibacterial properties, appears to be a promising and novel approach in biotherapy. In this overview, different scenarios for the control of Clostridium spp. by application of bacteriocins as therapeutic agents, also in synergistic combination with antibiotics, will be discussed.

A previous donor intervention trial found that therapeutic hypothermia reduced delayed graft function (DGF) after kidney transplantation. This retrospective cohort study nested in the randomized dopamine trial (ClinicalTrials.gov identifier: NCT000115115) investigates the effects of spontaneous donor hypothermia (core body temperature

BackgroundOverweight and abdominal obesity, in addition to medical conditions such as high blood pressure, high blood sugar and triglyceride levels, are typical risk factors associated with metabolic syndrome. Yet, considering the complexity of factors and underlying mechanisms leading to these inflammatory conditions, a deeper understanding of this area is still lacking. Some probiotics have a reputation of a relatively-long history of safe use, and an increasing number of studies are confirming benefits including anti-obesity effects when administered in adequate amounts. Recent reports demonstrate that probiotic functions may widely differ with reference to either intra-species or inter-species related data. Such differences do not necessarily reflect or explain strain-specific functions of a probiotic, and thus require further assessment at the intra-species level. Various anti-obesity clinical trials with probiotics have shown discrepant results and require additional consolidated studies in order to clarify the correct dose of application for reliable and constant efficacy over a long period.MethodsThree different strains ofLactobacillus sakeiwere administered in a high-fat diet induced obese murine model using three different doses, 1 × 1010, 1 × 109and 1 × 108CFUs, respectively, per day. Changes in body and organ weight were monitored, and serum chemistry analysis was performed for monitoring obesity associated biomarkers.ResultsOnly one strain ofL. sakei(CJLS03) induced a dose-dependent anti-obesity effect, while no correlation with either dose or body or adipose tissue weight loss could be detected for the other twoL. sakeistrains (L338 and L446). The body weight reduction primarily correlated with adipose tissue and obesity-associated serum biomarkers such as triglycerides and aspartate transaminase.DiscussionThis study shows intraspecies diversity ofL. sakeiand suggests that anti-obesity effects of probiotics may vary in a strain- and dose-specific manner.

Objective: To describe a patient with cryopyrin-associated periodic syndrome (CAPS) with an uncommon neurologic phenotype and a rare underlying genetic mutation. Results: Our patient had CAPS with a rare NLPR3 missense mutation (p.Tyr859Cys) in exon 6 with chorea as the major symptom. Clinical symptoms were associated with persistent inflammatory changes of the CSF and serum and included elevated anticardiolipin immunoglobulin G; MRI showed prolonged gadolinium enhancement of 2 chronic inflammatory lesions. Conventional immunosuppressive treatment with prednisolone and hydroxychloroquine was insufficient. Neurologic symptoms, laboratory/chemical measures, and MRI abnormalities almost completely normalized following interleukin (IL)–1β blockade with anakinra. Conclusions: This case is unique for its uncommon neurologic phenotype, the rare underlying genetic mutation, and the long course of the disease as well as almost complete recovery following appropriate therapy. In addition, the chronic inflammatory white matter lesions observed on brain MRI and the responsiveness to IL-1β blockade with anakinra are unusual.

Therapeutic hypothermia, hypothermic pulsatile machine perfusion (MP), and renal-dose dopamine administered to stable brain-dead donors have shown efficacy to reduce the dialysis requirement after kidney transplantation. In a head-to-head comparison of the three major randomized controlled trials in this field, we estimated the number-needed-to-treat for each method, evaluated costs and inquired into special features regarding long-term outcomes. The MP and hypothermia trials used any dialysis requirement during the first postoperative week, whereas the dopamine trial assessed >1 dialysis session as primary endpoint. Compared to controls, the respective rates declined by 5.7% with MP, 10.9% with hypothermia, and 10.7% with dopamine. Costs to prevent one endpoint in one recipient amount to approximately $17 000 with MP but are negligible with the donor interventions. MP resulted in a borderline significant difference of 4% in 3-year graft survival, but a point of interest is that the preservation method was switched in 25 donors (4.6%) for technical reasons. Graft survival was not improved with dopamine on intention-to-treat but suggested an exposure-response relationship with infusion time. MP was less efficacious and cost-effective to prevent posttransplant dialysis. Whether the benefit on early graft dysfunction achieved with any method will improve long-term graft survival remains to be established.

Overweight and obesity are considered as a major cause of various conditions related to metabolic syndrome. Yet, considering the complex interacting factors leading to pathogenicity and underlying mechanisms, it remains a poorly defined area. Some probiotics have a reputation of a relatively long history of safe use, and an increasing number of studies are confirming benefits including anti-obesity effects when administered in adequate amounts. Recent reports demonstrate that probiotic functions may widely differ with reference to either intra-species or inter-species related data. Such differences do not necessarily reflect or explain strain specific functions of a probiotic, and thus require further assessment at the intra-species level. Various anti-obesity clinical trials with probiotics have shown discrepant results and require more consolidated studies in order to clarify the correct dose of application for reliable and constant efficacy over a long period. In this study three different strains of Lactobacillus sakei were administered in a high fat diet induced obese murine model using three different doses, 1x1010 CFU, 1x109 CFU and 1x108 CFU, respectively, per day. Changes in body and organ weight were monitored, and serum chemistry analysis was performed for monitoring obesity associated biomarkers. The results show that only one strain of L. sakei (CJLS03) induced a dose dependent anti-obesity effect, while no correlation with either dose or body and adipose tissue weight loss could be detected for the other two L. sakei strains (L338 and L446). The body weight reduction mainly correlated with adipose tissue and obesity associated serum biomarkers such as triglycerides. This study suggests that anti-obesity effects of probiotics may vary in a strain and dose specific manner.

As normal inhabitants of diverse ecosystems, including the human gastrointestinal tract, the enterococci, and especially the two species Enterococcus faecalis and Enterococcus faecium, can be considered ubiquitous with regard to our natural environment. E. faecium has gained special importance thanks to beneficial strains marketed as probiotics, and because of its beneficial role in traditional fermented foods such as artisanal cheeses in some Southern European countries. Yet, following reports on the increasing association of some enterococcal strains with nosocomial infections such as endocarditis and bacteraemia, it became evident that strains from clinical origin are frequently highly resistant to ‘last-defence-line’ antibiotics such as the glycopeptide derivatives. For this reason enterococci have been classified in risk group 2 in the European Directive 93/88. With this paper it is intended to clarify the uncertain situation around the safety of the species E. faecium, also with referring to intra-species heterogeneity. In fact, well established scientific and surveillance data support the safety of some probiotic E. faecium strains for both human and animal applications. As a model, summarising yet extensive information is provided on the efficacy and safety of E. faecium SF68®, a pharmaceutical probiotic with a long history of safe use. We propose the approach presented in this review as a model for the evaluation of safety of probiotic strains of this species.

Whether organs from donors after brain death (DBD) with acute kidney injury (AKI) should be accepted for transplantation is still a matter of debate.This was a retrospective, center-based, matched cohort study of 33 renal transplant patients who received a renal allograft from a DBD with AKI. Sixty-five kidney transplants without donor AKI transplanted directly before and after the index transplantation served as controls.All AKI donors were classified according to RIFLE criteria: 9.1 % Risk, 54.6 % Injury, and 36.4 % Failure. Mean serum creatinine was 2.41 ± 0.88 mg/dL at procurement and 1.06 ± 0.32 mg/dL on admission. AKI donors had lower 24-h urine production (3.22 ± 1.95 vs. 4.59 ± 2.53 L, p = 0.009) and received more frequently noradrenaline (93.9 vs. 72.3 %, p = 0.02) and/or adrenaline (15.2 vs. 1.5 %, p = 0.02). Recipient and transplant characteristics were similar except a more favorable HLA match in control patients (p = 0.01). Hemodialysis posttransplant was more frequently used in AKI recipients (14/33 [42.4 %] vs. 18/65 [27.7 %], p = 0.17). While significant elevations in serum creatinine were noted in these patients until 10 days after transplantation, this difference lost statistical significance by day 14. One-year graft survival was very similar when comparing the groups (93.6 % [95 % CI 76.8-98.4 %] vs. 90.3 % [95 % CI 79.6-95.5 %], log rank p = 0.58).Kidneys from AKI donors can be transplanted with excellent intermediate prognosis and should not be discarded.

Aims Although peroxisome proliferator-activated receptors (PPARs)α/γ dual agonists can be beneficial for treatment of dyslipidemia in patients with type 2 diabetes, their use is limited owing to various side effects, including body weight gain, edema, and heart failure. We aimed to demonstrate that amodiaquine, an antimalarial agent, has potential as a PPARα/γ dual agonist with low risk of adverse effects. Methods We screened a Prestwick library (Prestwick Chemical; Illkirch, France) to identify novel PPARα/γ dual agonists and selected amodiaquine (4-[(7-chloroquinolin-4-yl)amino]-2-[(diethylamino)methyl]phenol), which activated both PPAR-α & -γ, for further investigation. We performed both in vitro, including glucose uptake assay and fatty acid oxidation assay, and in vivo studies to elucidate the anti-diabetic and anti-obesity effects of amodiaquine. Results Amodiaquine selectively activated the transcriptional activities of PPARα/γ and enhanced both fatty acid oxidation and glucose uptake without altering insulin secretion in vitro. In high-fat diet-induced obese and genetically modified obese/diabetic mice, amodiaquine not only remarkably ameliorated insulin resistance, hyperlipidemia, and fatty liver but also decreased body weight gain. Conclusion Our findings suggest that amodiaquine exerts beneficial effects on glucose and lipid metabolism by concurrent activation of PPARα/γ. Furthermore, amodiaquine acts as an alternative insulin-sensitizing agent with a positive influence on lipid metabolism and has potential to prevent and treat type 2 diabetes while reducing the risk of lipid abnormalities.

Africa has an age old history of production of traditional fermented foods and is perhaps the continent with the richest variety of lactic acid fermented foods. These foods have a large impact on the nutrition, health and socio-economy of the people of the continent, often plagued by war, drought, famine and disease. Sub-Saharan Africa is the world's region with the highest percentage of chronically malnourished people and high child mortality. Further developing of traditional fermented foods with added probiotic health features would be an important contribution towards reaching the UN Millennium Development Goals of eradication of poverty and hunger, reduction in child mortality rates and improvement of maternal health. Specific probiotic strains with documented health benefits are sparsely available in Africa and not affordable to the majority of the population. Furthermore, they are not used in food fermentations. If such probiotic products could be developed especially for household food preparation, such as cereal or milk foods, it could make a profound impact on the health and well-being of adults and children. Suitable strains need to be chosen and efforts are needed to produce strains to make products which will be available for clinical studies. This can gauge the impact of probiotics on consumers' nutrition and health, and increase the number of people who can benefit. Keywords: African traditional foods; Fermentation; GI infection; Malnutrition; Probiotics.

Background and objectives Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. Design, setting, participants, & measurements Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). Results Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0–32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. Conclusions We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

A rich variety of indigenous fruits and vegetables grow in Africa, which contribute to the nutrition and health of Africa's populations. Fruits and vegetables have high moisture and are thus inherently prone to accelerated spoilage. Food fermentation still plays a major role in combating food spoilage and foodborne diseases that are prevalent in many of Africa's resource disadvantaged regions. Lactic acid fermentation is probably the oldest and best-accepted food processing method among the African people, and is largely a home-based process. Fermentation of leafy vegetables and fruits is, however, underutilized in Africa, although such fermented products could contribute toward improving nutrition and food security in this continent, where many are still malnourished and suffer from hidden hunger. Fermentation of leafy vegetables and fruits may not only improve safety and prolong shelf life, but may also enhance the availability of some trace minerals, vitamins and anti-oxidants. Cassava, cow-peas, amaranth, African nightshade, and spider plant leaves have a potential for fermentation, as do various fruits for the production of vinegars or fruit beers and wines. What is needed to accelerate efforts for production of fermented leaves and vegetables is the development of fermentation protocols, training of personnel and scale-up of production methods. Furthermore, suitable starter cultures need to be developed and produced to guarantee the success of the fermentations.

Majority of global fermented foods is naturally fermented by culturalable and non-culturable microorganisms. Food fermentations represent an extremely valuable cultural heritage in most regions, and harbour a huge genetic potential of valuable but hitherto undiscovered strains. Holistic approaches for identification and complete profiling of both culturalable and non-culturable microorganisms in global fermented foods are interest to food microbiologists. The application of molecular and modern identification tools through culture-independent techniques has thrown new light on the diversity of a number of hitherto unknown and uncultivable microorganisms in naturally fermented foods. Functional bacterial groups (phylotypes) may be reflected by their mRNA expression in a particular substrate and not by mere DNA-level detection. An attempt is made here to review the microbiology of some global fermented foods and alcoholic beverages.

Enterococci belong to the lactic acid bacteria (LAB) and they are of importance in foods due to their involvement in food spoilage and fermentations, as well as their utilisation as probiotics in humans and slaughter animals. However, they are also important nosocomial pathogens that cause bacteraemia, endocarditis and other infections. Some strains are resistant to many antibiotics and possess virulence factors such as adhesins, invasins, pili and haemolysin. The role of enterococci in disease has raised questions on their safety for use in foods or as probiotics. Studies on the incidence of virulence traits among enterococcal strains isolated from food showed that some can harbour virulence traits, but it is also thought that virulence is not the result of the presence of specific virulence determinants alone, but is rather a more intricate process. Specific genetic lineages of hospital-adapted strains have emerged, such as E. faecium clonal complex (CC) 17 and E. faecalis CC2, CC9, CC28 and CC40, which are high risk enterococcal clonal complexes. These are characterised by the presence of antibiotic resistance determinants and/or virulence factors, often located on pathogenicity islands or plasmids. Mobile genetic elements thus are considered to play a major role in the establishment of problematic lineages. Although enterococci occur in high numbers in certain types of fermented cheeses and sausages, they are not deliberately added as starter cultures. Some E. faecium and E. faecalis strains are used as probiotics and are ingested in high numbers, generally in the form of pharmaceutical preparations. Such probiotics are administered to treat diarrhoea, antibiotic-associated diarrhoea or irritable bowel syndrome, to lower cholesterol levels or to improve host immunity. In animals, enterococcal probiotics are mainly used to treat or prevent diarrhoea, for immune stimulation or to improve growth. From a food microbiological point of view, the safety of the bacteria used as probiotics must be assured, and data on the major strains in use so far indicate that they are safe. The advantage of use of probiotics in slaughter animals, from a food microbiological point of view, lies in the reduction of zoonotic pathogens in the gastrointestinal tract of animals which prevents the transmission of these pathogens via food. The use of enterococcal probiotics should, in view of the development of problematic lineages and the potential for gene transfer in the gastrointestinal tract of both humans and animals, be carefully monitored, and the advantages of using these and new strains should be considered in a well contemplated risk/benefit analysis.

Objective.Since Wegener’s granulomatosis (WG) represents a relapsing disease, efforts have been made to reliably predict relapses using blood tests. Followup measures such as conventionally determined C-reactive protein (CRP), antineutrophil cytoplasmic antibody (C-ANCA) titer, and proteinase-3 (PR3) ELISA are applied. We evaluated whether during remission elevated highly sensitive CRP (hsCRP) precedes relapse as a marker of subclinical inflammation and thus might improve clinical assessment.Methods.We investigated 227 sera of 57 patients with WG: 74 sera collected from patients in remission who subsequently relapsed (before relapse), 30 sera collected during relapse, and 123 sera from patients in remission without relapse. We also distinguished between major and minor relapse. hsCRP, conventionally determined CRP (CRP), C-ANCA, PR3-ELISA, and erythrocyte sedimentation rate (ESR) were measured using commercial kits, and levels were correlated to clinical status.Results.Only hsCRP and ANCA titer, but not CRP levels, were higher in sera from patients who subsequently relapsed versus those who did not, indicating patients at risk. Levels of hsCRP, CRP, and ESR were higher in sera collected during relapse than in the sera before relapse. hsCRP, conventional CRP, and ESR were also higher in samples collected during major relapse than before major relapse. Looking at the levels just before relapse compared to previous levels during remission, none of these measures rose directly before the clinical manifestation of the relapse.Conclusion.Our study provides evidence for an additional value of hsCRP in the clinical assessment of patients with WG.

Traumatic optic neuropathy is a severe complication of a head or face trauma. Diagnosis is established by analyzing pupillary responses to light. Fundus examination and orbital CT scan help to localize the site of the lesion and may show a fracture involving the optic canal. Surgical decompression or megadose steroids are therapeutic options. No therapeutic approach has proven with sufficient evidence to be effective. Spontaneous improvement is definitely possible. Based on experiences in single cases direct compression of the optic nerve by bone fragments or optic nerve sheath haemorrhage are as a rule treated surgically. In all other cases usually high dose steroids are given without proven effectiveness.

Cranberry juice (Vaccinium macrocarpon) is a widely used and recommended North-American folk remedy for prophylaxis of urinary tract infections (UTI). Clinical trials have documented its efficacy in women with recurrent UTI, but so far not in other groups of patients. The composition of effective cranberry products and its dosage in UTI prophylaxis have not been defined. Intriguing experimental research has identified an anti-adhesive mechanism of cranberry juice that prevents docking of bacteria on host tissues. This efficacy mechanism can be traced in patients' urine following oral intake of cranberry products and appears to be due to proanthocyanidins with an A-type linkage of flavanols. The application of this anti-adhesion mechanism of cranberry-proanthocyandins is currently also investigated in other common diseases of bacterial pathogenesis, for example Helicobacter pylori-associated gastritis and dental caries/periodontal disease. The use of cranberry products appears to be safe and provide additional benefits by anti-oxidant and cholesterol-lowering activity.

BACKGROUND Mycophenolic acid (MPA) is used in the maintenance therapy of antineutrophil cytoplasm antibody-associated systemic vasculitis (AASV). MPA exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. The purpose of our study was to examine the correlation between clinical outcome and pharmacokinetic-pharmacodynamic (PD) relationships of MPA in patients with AASV. METHODS We studied 358 Caucasian control patients without any MPA therapy to examine basal IMPDH activity. Thirty Caucasian patients with AASV under maintenance therapy with mycophenolate mofetil (MMF) underwent therapeutic drug monitoring. RESULTS We observed a high interindividual variability with regard to basal IMPDH activity in patients without any MPA treatment (0.8-35 nmol/mg protein/h). Patients were followed for a mean (±SD) period of 22 ± 8 months. During the observation period, seven patients had a relapse with an elevated Birmingham Vasculitis Activity Score of 9.2 ± 6. The basal IMPDH activity (Abasal) in patients who subsequently relapsed was raised at baseline, before receiving their first dose of MMF, and further increased at the time of relapse, when compared with stable patients. Patients with a relapse during the maintenance therapy had significantly higher levels of IMPDH activity [IMPDH enzyme activity curve (AEC) (0-12)] than stable patients (P = 0.001), indicating inadequate IMPDH suppression. MPA-AUC (0-12) was significantly decreased in relapse patients, in contrast to stable patients (P < 0.05). CONCLUSIONS Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients.

Most probiotic foods are milk based, although many fermented cereals, also with added probiotic cultures, are appearing on the market. Cereals have a high nutritional value (vitamins, proteins, dietary fibre, energy and minerals) and are cultivated on more than 73% of agricultural soil while contributing to more than 60% of the world's food production. In addition, cereal-based fermented food products have a long history as products with beneficial properties. Lactic acid bacteria may contribute to the extension of the shelf life of the products by producing various antimicrobial substances, including bacteriocins, lactic acid, hydrogen peroxide, fatty acids, diacetyl and other low-molecular-weight compounds during fermentation.

Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the central nervous system. Mostly young adults present with a variety of different symptoms due to the multiple localisations of the inflammatory lesions. Up to one-third of MS patients experience symptoms of optic neuritis as the initial symptom. That is the reason why the ophthalmologist often is the first physician contacted by patients later on diagnosed with MS. Today, it is known that there is already a significant irreversible axonal loss in MS patients progressing from the beginning of the disease. Therefore early, diagnosis and application of available therapeutic options are necessary for the patient's benefit. The therapeutic aim in early immunomodulatory treatment is to decrease the number of relapses and to slow down the development of clinical disability. This interdisciplinary overview presents guidelines for the clinical routine: how to assess the individual risk of each patient and how to treat the patient in accordance with current pathogenic, diagnostic and therapeutic knowledge.

Background: Antineutrophil cytoplasmic antibodies (ANCAs) are considered by some investigators to be sensitive markers of disease activity and have been suggested to predict relapse and guide therapeutic decisions. Studies using serial ANCA monitoring in patients with ANCA-associated vasculitis (AASV) have yielded controversial results during the last 15 years. To assess the diagnostic value of serial ANCA testing in the follow-up of patients with AASV, we conducted a systematic review of the available literature. Methods: Studies were identified by a comprehensive search of the PubMed and BIOSIS+/RRM databases, as well as hand searching. Method quality of all eligible studies was assessed with respect to external and internal validity according to established criteria for diagnostic studies. Results: Twenty-two studies met our inclusion criteria, including a total of 950 patients. Whereas generalizability was not a major problem, assessment of internal validity showed that only a minority of studies reported the combination of consecutive patient recruitment, prospective data collection, and independent determination of both index and reference tests, considered as the ideal for diagnostic test studies. Quantitative meta-analytic calculations were not conducted because of the presence of considerable method heterogeneity. Conclusion: The presence of considerable methodological heterogeneity combined with methodological shortcomings with respect to internal validity in the majority of included studies preclude firm conclusions from the available literature concerning the clinical value of serial ANCA determinations for monitoring the follow-up of patients with AASV.

Traditional fermentation of cassava is dominated by a lactic acid bacteria (LAB) population. Fermentation is important for improving product flavour and aroma as well as safety, especially by reduction of its toxic cyanogenic glucosides. The production of Gari from cassava in Benin typically occurs on a household or small industrial scale, and consequently suffers from inconsistent product quality and may not always be safe for consumption. Therefore, the diversity of LAB from a typical cassava fermentation for the preparation of Gari, and their technologically relevant characteristics were investigated with a view towards selection of appropriate starter cultures. A total of 139 predominant strains isolated from fermenting cassava were identified using phenotypic tests and genotypic methods such as rep-PCR and RAPD-PCR. DNA-DNA hybridisation and sequencing of the 16S rRNA genes were done for selected strains. Lactobacillus plantarum was the most abundantly isolated species (54.6% of isolates), followed by Leuconostoc fallax (22.3%) and Lactobacillus fermentum (18.0%). Lactobacillus brevis, Leuconostoc pseudomesenteroides and Weissella paramesenteroides were sporadically isolated. The L. plantarum strains were shown to be better acid producers and capable of faster acid production than the L. fallax or L. fermentum strains. The incidence of beta-glucosidase (linamarase) activity was also highest among strains of this species. Production of antagonistic substances such as H2O2 and bacteriocins, however, was more common among L. fallax and L. fermentum strains. Strains of all three species were capable of utilising the indigestible sugars raffinose and stachyose. Therefore, a starter culture containing a mixture of strains from all three species was recommended.

Enterococci form part of the lactic acid bacteria (LAB) of importance in foods. They can spoil processed meats but they are on the other hand important for ripening and aroma development of certain traditional cheeses and sausages, especially those produced in the Mediterranean area. Enterococci are also used as human probiotics. However, they are important nosocomial pathogens that cause bacteraemia, endocarditis and other infections. Some strains are resistant to many antibiotics, but antibiotic resistance alone cannot explain the virulence of some of these bacteria. Virulence factors such as adhesins, invasins and haemolysin have been described. The role of enterococci in disease has raised questions on their safety for use in foods or as probiotics. Studies on the incidence of virulence traits among enterococcal strains isolated from food showed that some harbour virulence traits and generally, Enterococcus faecalis harbours more of them than Enterococcus faecium. Regulations in Europe stipulate that safety of probiotic or starter strains is the responsibility of the producer; therefore, each strain intended for such use should be carefully evaluated. For numerous questions, immediate answers are not fully available. It is therefore suggested that when considering an Enterococcus strain for use as a starter or probiotic culture, it is imperative that each particular strain should be carefully evaluated for the presence of all known virulence factors. Ideally, such strains should harbour no virulence determinants and should be sensitive to clinically relevant antibiotics. In general, E. faecium appears to pose a lower risk for use in foods, because these strains generally harbour fewer recognised virulence determinants than E. faecalis. Generally, the incidence of such virulence determinants among E. faecium strains is low, as compared to E. faecalis strains, probably as a result of the presence of pheromone-responsive plasmids.

A patient initially presented with anginal symptoms and a positive stress thallium test. An arteriovenous malformation in the right coronary artery causing a suspected coronary “steal syndrome” was subsequently discovered. This was treated with a microcoil embolization technique in lieu of the traditional surgical approach and this technique is described in detail. The patient had successful clinical, nuclear, and angiographic outcomes. (J Interven Cardiol 2003;16:347–350)

Despite important therapeutic improvements, permanent organ failure may develop in primary systemic vasculitides and affect the heart, the lungs, and especially the kidneys. In systemic vasculitides associated with antineutrophil cytoplasmic antibodies (AASV), end-stage renal failure develops in 20% of cases. Renal transplantation became a beneficial option in these patients, with a graft and patient survival comparable to that in nondiabetic patients. This review summarizes the current knowledge on indications and contraindications for renal transplantation in AASV and discusses the impact of posttransplant immunosuppression on the course of the patients.

New models for the Maddock and spiral shearing sections have been developed, employing three-dimensional finite element analysis (3D FEA). These models describe the pressure-throughput and power consumption behavior of the shearing sections for both the extrusion and the injection molding process and have been implemented in the REX 6.0 and PSI 4.0 simulation software. As a consequence it is now possible to describe the process behavior of these shearing sections within just a few seconds with the accuracy of FEA calculations. Actual Maddock shearing section (left) and actual spiral shearing section (right).

It is almost impossible to cover all the options available for the treatment of premenstrual syndrome and premenstrual dysphoric disorder. This article discusses the most common and relevant options.

The wide variety and the socio-economic and dietary importance of traditional fermented milk products of Ethiopia are discussed in this paper. Information on the microbiology of these products is sparse and has relevance to those organisms associated with spoilage and to those considered desirable for fermentation. There is a clear need to improve the production of African foods and beverages [Int. J. Food Microbiol. 18 (1993) 85]. The objective of this review was to document traditional technology used and information on the microbiology of the products, and to identify various constraints to the development and commercialisation of fermented milk products. Thereby the major problems and potential areas for improvement are pointed out. Ergo, the most important traditional product resembles yoghurt and, as the other traditional products, is prepared by "spontaneous" fermentation, commonly initiated by either "back slopping" or by repeated use of the same utensil. Other products include traditional fermented curd or ititu, traditional butter or kibe, neter kibe or traditional ghee, ayib resembling cottage cheese, arrera or defatted buttermilk and augat or traditional whey.

The effects of barley variety, malting, brewing technology, brewer's yeast and bacterial contamination on the biogenic amine content of beer have been investigated. Our results showed that barley variety had a detectable effect on amine content, and this was also reflected in the amino acid decarboxylase activities of the samples. Investigations established that histamine in malt did not originate from barley but was due to microbial contamination. During wort processing, significant increases of agmatine and putrescine occurred, together with decreases for spermidine and spermine. As the histamine synthesising ability of different Lactobacillus strains are quite different, there was no correlation between the histamine level of beer and the bacterial contamination of wort and pitching yeast, respectively. Total amine concentrations of bottled beer are significantly influenced by the brewing technology and to a much lesser extent by the applied barley variety. The histamine content of beer is a good indicator for hygienic conditions of barley storage, malting and brewing, as the histamine content of the product does not originate from barley or from the malt.

Enterococci are gram-positive bacteria and fit within the general definition of lactic acid bacteria. Modern classification techniques resulted in the transfer of some members of the genus Streptococcus, notably some of the Lancefield's group D streptococci, to the new genus Enterococcus. Enterococci can be used as indicators of faecal contamination. They have been implicated in outbreaks of foodborne illness, and they have been ascribed a beneficial or detrimental role in foods. In processed meats, enterococci may survive heat processing and cause spoilage, though in certain cheeses the growth of enterococci contributes to ripening and development of product flavour. Some enterococci of food origin produce bacteriocins that exert anti-Listeria activity. Enterococci are used as probiotics to improve the microbial balance of the intestine, or as a treatment for gastroenteritis in humans and animals. On the other hand, enterococci have become recognised as serious nosocomial pathogens causing bacteraemia, endocarditis, urinary tract and other infections. This is in part explained by the resistance of some of these bacteria to most antibiotics that are currently in use. Resistance is acquired by gene transfer systems, such as conjugative or nonconjugative plasmids or transposons. Virulence of enterococci is not well understood but adhesins, haemolysin, hyaluronidase, aggregation substance and gelatinase are putative virulence factors. It appears that foods could be a source of vancomycin-resistant enterococci. This review addresses the issue of the health risk of foods containing enterococci.

To find serologic markers of disease activity in patients with Churg-Strauss syndrome (CSS) linked to possible pathogenetic mechanisms by studying endothelial cell damage (soluble thrombomodulin [sTM]) in relation to T cell and eosinophil activation markers (soluble interleukin-2 receptor [sIL-2R] and eosinophil cationic protein [ECP]), and the presence of autoantibodies (antineutrophil cytoplasmic antibodies [ANCA] and anti-endothelial cell antibodies [AECA]) during both active and inactive phases of disease.Sixteen consecutive patients who fulfilled the 1992 Chapel Hill definition of CSS were studied over a period of 4.5 +/- 3.9 years (mean +/- SD). ECP was detected by Columbo immunocapture (immunoCAP) assay, sIL-2R and sTM by enzyme-linked immunosorbent assay (ELISA), AECA by cell ELISA, and ANCA by indirect immunofluorescence and ELISA.In patients with active disease, ECP (8.4 +/- 90 units/ml), sIL-2R (3,725 +/- 2,310 units/ml), and sTM levels (5.5 +/- 2.9 units/liter) were significantly elevated compared with those in remission. Levels of sIL-2R showed a close correlation with levels of sTM (r = 0.75, P0.05). Interestingly, during remission, sIL-2R levels remained elevated in 4 of 7 patients, although the erythrocyte sedimentation rate, C-reactive protein level, and sTM level returned to the normal range (levels1,000 units/ml were associated with relapse). ANCA were found in only 7 patients (4 had classic ANCA, 3 had perinuclear ANCA), and AECA in 11 sera from 8 patients. In contrast to AECA, ANCA were associated with active disease.In its active state, CSS is associated with markedly increased levels of sIL-2R and ECP, indicating T cell and eosinophil activation. Elevated sTM is a sign of endothelial cell damage that can be closely linked to T cell activation, as indicated by increased sIL-2R levels.

An overview on the role and potential of microorganisms in traditional food fermentations is given. Prospects for the implementation of starter cultures for homescale food fermentations are discussed against the background of the present situation, socio-economic and rural/logistic constraints, and the potential for improvement of traditional processes. Special attention is given to the African situation and the well-accepted lactic fermented, traditional foods. Perspectives are given on the improvement of the nutritional value and the overall product safety, with reference to strain selection on the basis of particular phenotypic and technical features.

Purpose Vascular injury plays an important pathophysiological role in vasculitis. Soluble serum thrombomodulin (sTM), a promising marker of endothelial cell injury, is released into the circulating blood following cell damage and was therefore investigated as a parameter of disease activity in patients with Wegener's granulomatosis (WG) and various other vasculitides. Patients and methods One hundred and ninety-seven sera of 102 patients with historically proven WG of different disease activity and 41 sera of patients with other vasculitides at their active stage were investigated (12 Takayasu arteritis [TA], 7 giant cell arteritis [GCA], 10 polyarteritis nodosa [PAN], 12 Behcet's disease [BD]). The sera were examined for the levels of sTM and sE-selectin (CD62E) by enzyme-linked immunosorbent assay (ELISA) and for the presence of classical anti-neutrophil cytoplasmic antibodies (cANCA) by indirect immunofluorescence (IIF). The disease activity was evaluated according to the clinical symptoms and organ involvement. Results A significant increase of sTM levels compared with control values (26 ± 2 ng/ml) was found in active WG, TA, GCA, PAN, and BD: limited active WG: 63 ± ng/ml; generalized active WG: 119 ± 15 ng/ml; limited WG, partial remission: 60 ± 5 ng/ml; generalized WG, partial remission: 75 ± 7 ng/ml; active TA: 36 ±; active GCA: 36 ± 4 ng/ml, active PAN: 33 ± 2 ng/ml, active BD: 40 ± 4 ng/ml. Limited and generalized WG in complete remission did not have elevated levels of sTM. sTM values closely reflected relapses and therapy-induced remissions of WG. Elevated cANCA titers were correlated as well with the disease activity in WG but more weakly than sTM levels. In contrast, sE-selectin values were not significantly correlated with the disease activity and the course of disease. Conclusions sTM is a promising serological marker of disease activity and progression in active limited and generalized WG and other vasculitides reflecting the degree of endothelial cell damage. sTM might prove to be a clinically useful marker for therapeutic considerations.

Chronic Helicobacter pylori-associated gastritis is now widely accepted as one of the most important pathogenic factors in duodenal ulcer disease. However, little is known about for how long patients remain free of duodenal ulcer relapses after H. pylori infection has been cured. In the present study, we investigated remission time during a 5-year follow-up period after anti-H. pylori treatment.The patients were randomly allocated to treatment with either a combination of 3 x 600 mg bismuth subsalicylate and 2 x 1000 mg amoxycillin or 3 x 600 mg bismuth subsalicylate monotherapy. Endoscopy, including histological and microbiological examination of biopsies, was performed 4 weeks after termination of treatment and after 1 and 2 years. During the third, fourth and fifth years of the follow-up period, patients were monitored twice a year for symptoms compatible with ulcer relapse and for their use of anti-ulcer medication. Endoscopic and histological examinations were carried out whenever symptoms occurred.Of 56 evaluated patients, 47 showed healing of ulcers after bismuth subsalicylate plus amoxycillin compared with 44 of 57 after bismuth subsalicylate monotherapy. H. pylori infection was cured in 52% (29 of 56) of the patients after combined therapy and in 4% (2 of 57) after the monotherapy. The cumulative duodenal ulcer relapse rates after 5 years were 38% (18 of 47) after the combined therapy and 75% (33 of 44) after the monotherapy. In patients who were cured of H. pylori infection, the cumulative duodenal ulcer relapse rate after 5 years was 9.7% (3 of 31), compared with 81.7% (49 of 60) in those patients who remained H. pylori-positive after treatment (P0.001). In two of the three patients who suffered duodenal ulcer relapse after being cured of H. pylori infection, H. pylori was present again at the time of relapse.The data suggest that curing H. pylori infection results in long-term cure of duodenal ulcer disease and that duodenal ulcer relapses in successfully treated patients are most often associated with H. pylori reinfection.

The paper describes an electron beam lithography system for structures as small as 10nm and pattern samples produced on it. The system works with electron energies from 20keV down to 1keV. A special objective lens allows to realize probes of 5nm diameter for the lower energy range. Depending on how much energy is applied, the electrons will penetrate more or less deeply into the material. This may be used to create three-dimensional profiles in the resist. Provided in the system is a quasi-continuous path control to generate protracted curved structures with minimum edge roughness. Automatic marker detection algorithms and metric coordinate-control facilities enable the use of mix-and-match technologies.

Objective. To assess the effectiveness of pulse cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG) and to identify the patients who are responsive to the treatment. Methods. The prospective study included 43 patients with biopsy-proven WG. Clinical, radiographic, laboratory, and immunologic data were evaluated for predicitive values regarding the outcome of pulse CYC therapy. Results. Only 42% of the patients showed complete or partial remission that lasted at least 6 months after cessation of pulse CYC therapy. These responders had a higher frequency of disease activity limited to the upper and lower respiratory tract (39%, versus 8% in the nonresponder group; P < 0.05) and had lower titers of classic antineutrophil cytoplasmic antibody (cANCA) prior to treatment (

This paper presents an overview of the origin and importance of biogenic amines found in foods, with special reference to biogenic amines resulting from the metabolic activities of food-associated microorganisms. Compared with foods of animal origin (e.g. milk and meat products), relatively little information is available on the levels of biogenic amines in vegetable foods and in novel and prepacked convenience foods.

Introduction As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). Methods Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. Results A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus - National Assessment - systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day. Conclusions Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials. Trial registration ClinicalTrials.gov: NCT00709722

Objective.To investigate the operating characteristics of the American College of Rheumatology (ACR) traditional format criteria for Wegener’s granulomatosis (WG), the Sørensen criteria for WG and microscopic polyangiitis (MPA), and the Chapel Hill nomenclature for WG and MPA. Further, to develop and validate improved criteria for distinguishing WG from MPA by an artificial neural network (ANN) and by traditional approaches [classification tree (CT), logistic regression (LR)].Methods.All criteria were applied to 240 patients with WG and 78 patients with MPA recruited by a multicenter study. To generate new classification criteria (ANN, CT, LR), 23 clinical measurements were assessed. Validation was performed by applying the same approaches to an independent monocenter cohort of 46 patients with WG and 21 patients with MPA.Results.A total of 70.8% of the patients with WG and 7.7% of the patients with MPA from the multicenter cohort fulfilled the ACR criteria for WG (accuracy 76.1%). The accuracy of the Chapel Hill criteria for WG and MPA was only 35.0% and 55.3% (Sørensen criteria: 67.2% and 92.4%). In contrast, the ANN and CT achieved an accuracy of 94.3%, based on 4 measurements (involvement of nose, sinus, ear, and pulmonary nodules), all associated with WG. LR led to an accuracy of 92.8%. Inclusion of antineutrophil cytoplasmic antibodies did not improve the allocation. Validation of methods resulted in accuracy of 91.0% (ANN and CT) and 88.1% (LR).Conclusion.The ACR, Sørensen, and Chapel Hill criteria did not reliably separate WG from MPA. In contrast, an appropriately trained ANN and a CT differentiated between these disorders and performed better than LR.

SUMMARY The past decade has seen an explosion of data on the new group of autoantibodies known collectively as ANCA (anti-neutrophil cytoplasmic antibodies). ANCA are specific for granule proteins of granulocytes and monocytes and induce distinct fluorescence patterns, e.g. the cytoplasmic (classic) cANCA and the perinuclear pANCA. cANCA is induced by antibodies directed against Proteinase 3 (PR3; PR3-ANCA) in about 90% of all ANCA-positive sera, and pANCA is induced by antibodies against myeloperoxidase (MPO; MPO-ANCA) in about 40%. A further staining pattern, which does not have a clear cut association with a distinct granule protein, is sometimes seen in chronic inflammatory bowel diseases. PR3-ANCA are serological markers for Wegener's granulomatosis (WG) and MPO-ANCA are associated with certain subtypes of primary vasculitides. Evidence exists that both the autoantigen and ANCA participate in the pathogenesis of at least the group of ‘ANCA-associated vasculitides’.

Objectives. MMF is cleaved in the acidic milieu of the gastric compartment. However, its absorption might be impeded by proton pump inhibitors (PPIs), which suppress acid production and thus increase stomach pH. Since PPIs are widely used, it is useful to clarify whether the total drug amount of MMF is available in patients undergoing PPI treatment. Methods. We analysed 36 patients with autoimmune diseases under stable MMF maintenance therapy. Twenty-three patients received co-medication with pantoprazole; 13 patients received no treatment with PPIs or antacids. To assess the immunosuppressive potency, we measured mycophenolic acid levels and inosin monophosphate dehydrogenase (IMPDH) activity with a validated HPLC method in plasma samples collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h after oral administration. Results. The mean MMF dosage of the non-PPI patients was 770 (249) mg/12 h and 771 (291) mg/12 h in pantoprazole-treated patients (NS). The total area under the curve of MMF showed a 37% reduction in PPI patients vs those treated with no PPIs (P < 0.01), and the maximum peak concentration of MMF was 60% lower in the pantoprazole patients (P < 0.001). The MMF exposure correlated with the inhibition of IMPDH activity. The area of enzyme activity curve was 42% higher in the PPI patients (P < 0.01). Conclusions. The co-medication of pantoprazole with MMF significantly influences the drug exposure and immunosuppressive potency of MMF in patients with autoimmune diseases. This finding might at least partly explain the different outcomes in studies using MMF for maintenance therapy.