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Background The landscape of inflammatory bowel disease (IBD) treatment is rapidly expanding with the development of new therapeutic options. Risankizumab (Skyrizi®), a humanised IgG monoclonal antibody that targets the p19 subunit of IL-23, was developed for the treatment of immunological and inflammatory disorders, and recently began to be investigated also in the field of IBD. Most patients who receive Risankizumab do so as part of clinical trials, but there are a number of patients with severe refractory disease who have received it as a compassion treatment and they present preliminary Real-World data for this drug. Aim to present the real-world data of patients with severe refractory IBD who received Risankizumab as a compassion treatment. Methods Retrospective Israeli multicenter study from 6 tertiary IBD centers (Shaare Zedek medical center, Wolfson, Ichilov, Hadassah , Sheba and Barzilai ) on 21 patients with severe refractory IBD (18 CD, 3 UC) who received Risankizumab (IV 600 mg at 0, 4, 8 weeks; then SC 180 or 360 mg SC every 8 weeks) as compassionate treatment with a median follow up of 30 weeks (4-52 weeks). Results Although some of the clinical and laboratory parameters are still being collected, we can present some trends. 21 patients were included in the analysis. 17 /21 were after ustekinumab failure. At week 12, there was a significant reduction in Harvey-Bradshaw index (HBI) for Crohn's disease, in CRP values and Calprotectin as compared with the baseline data (10.13 to 4.82, p=0.03; 4.16 to 1.62, p=0.004; 3758 to 961, p=0.02, Respectively). In addition, there was a reduction in the percentage of steroids dependent patients (0.44 to 0.14, p=0.07). In the margins of the study, it is worth noting that particularly patients with difficult and resistant disease, who were TPN dependent or on the verge of surgery, as a result of treatment were weaned from TPN or were able to avoid surgery. Conclusion According to real-world data, Risankizumab holds a great therapeutic promise even for patients with particularly serious and resistant diseases.

Loading pattern optimization enables longer irradiation cycles while still maintaining the ability to safely operate and shutdown the reactor. The loading pattern optimization problem is multi-objective and is characterized by a huge nonlinear discrete search space. Its complexity grows exponentially with the number of fuel assemblies in the core. However, in-core fuel management is an essential part of routine work in a nuclear reactor, hence optimized usage of the fuel inventory enables the economic and efficient utilization of resources. This study is a proof-of-concept for the hypothesis that adjoint-based neutron importance functions can be used for the optimization process of the core loading pattern. New optimization techniques are developed in order to demonstrate the successful utilization of adjoint-based functions as the optimization driving force. Different importance functions are developed and studied. It is demonstrated that the physical insight obtained from the importance function can be used for the optimization of loading patterns. Eventually, this new technique should be integrated into a stochastic optimization algorithm, e.g., evolutionary algorithms, in order to accelerate and improve existing optimization algorithms.

A genetic algorithm based on novel genetic operators is implemented for the problem of nuclear fuel loading pattern optimization. This is achieved using rank selection or tournament selection and novel crossover operator and fitness function constructions, e.g., improved crossover and mutation operators by considering the chromosomes as permutations (which is a specific feature of the loading pattern problem) and the “stage fitness function” that separates the different objectives of the optimization. Another novel feature of the algorithm is the consideration of the geometric nature of the problem and the desired loading pattern solutions. A new geometric crossover is developed to utilize this geometric knowledge and its implementation exhibits good results. A comprehensive study is performed on the effect of different adaptive mutation strategies on the performances of the algorithm. The new algorithm is implemented and applied to two benchmark problems and used to study the effect of boundary conditions on the symmetry of the obtained best solutions.

Antiphospholipid syndrome (APS) is characterised by the development of thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). These antibodies are currently considered to be pathogenic autoantibodies directed mainly against phospholipid-binding proteins such as β2-glycoprotein-I (β2GPI). Studies on experimental APS models have proven that molecular mimicry between β2GPI-related synthetic peptides and structures within bacteria, viruses, tetanus toxoid and cytomegalovirus can cause experimental APS. In addition to molecular mimicry, the explanation of how microbial and viral infections might set off APS must account for bystander activation, the alteration of self-molecular changes and a “second hit”.

The microorganisms Escherichia coli DH5 alpha and Bacillus thuringiensis HD-1 show an increased tolerance to freeze-drying when dried in the presence of the disaccharides trehalose and sucrose. When the bacteria were dried with 100 mM trehalose, 70% of the E. coli and 57% of the B. thuringiensis organisms survived, compared with 56 and 44%, respectively, when they were dried with sucrose. Only 8% of the E. coli and 14% of the B. thuringiensis organisms survived drying without the sugars. Fourier transform infrared spectroscopy was used to investigate the role of membrane phase transitions in the survival of the organisms during drying and rehydration. Both E. coli and B. thuringiensis showed an increase of 30 to 40 degrees C in the temperature of their phospholipid phase transition when dried without the sugars, while phase transition temperatures of those dried with the sugars remained near those of the hydrated cells. A Fourier transform infrared spectroscopy microscope made it possible to investigate the effects of drying on the protein structure in the intact cells. The amide II peak shifts from 1,543 cm-1 in the hydrated cells to about 1,533 cm-1 in the cells dried without sugar. There is no shift in the amide II peak when the cells are dried with trehalose or sucrose. We attribute the increased survival to the sugars' ability to lower the membrane phase transition temperature and to protect protein structure in the dry state.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients treated with infliximab for Crohn's disease (CD) frequently require intensified dosage due to loss of response. There are scant data regarding the efficacy of shortening the dosing interval to 6 weeks.We sought to investigate the efficacy of a once every 6 weeks' strategy compared with dose-doubling.This work was a multicentre retrospective study of infliximab-treated CD patients who required dose escalation. The clinical outcome of patients treated by intensification to 5 mg/kg/6 weeks (6-week group) was compared with the outcome of patients whose infliximab was double-dosed (10 mg/kg/8 weeks or 5 mg/kg/4 weeks).Ninety-four patients (mean age: 29.8 years) were included in the study, 55 (59%) in the 6-week group and 39 (41%) in the double-dose group. Demographics and disease characteristics were similar between the two groups, although patients with re-emerging symptoms 5-7 weeks postinfusion were more likely to receive 5 mg/kg/6 weeks dosing (OR: 3.4, 95% CI: 1.4-8.8, P0.01). Early response to dose-intensification occurred in 69% of patients in the 6-week group and 67% in the double-dose group (P = N.S.). Regained response was maintained for 12 months in 40% compared with 29% of the patients respectively (P = N.S.).In CD patients who lost response to standard infliximab dose, especially when symptoms re-emerge 5-7 weeks postinfusion, shortening the dosing interval to 6 weeks appears to be at least as effective as doubling the dose to 10 mg/kg or halving the infusion intervals to once in 4 weeks.

Mammalian bite wounds are commonly encountered in the emergency department. When patients come early (

We hypothesize that hypoglycaemia in insulin-treated diabetic patients may result from gastric emptying abnormalities causing insulin and food absorption mismatching. We tested gastric emptying in insulin-treated diabetic patients with unexplained hypoglycaemia and without dyspepsia and in diabetic patients without hypoglycaemia, prospectively. Thirty-one diabetic patients with unexplained hypoglycaemic events within 2 h of insulin injection and 18 insulin-treated diabetic patients without hypoglycaemic events underwent gastric emptying breath tests, glycaemic control and autonomic nerve function. Gastric emptying tests were abnormal in 26 (83.9%) and in four (22.2%) patients with and without hypoglycaemia, respectively (P0.001). Gastric emptying was significantly slower in hypoglycaemic diabetic patients (t1/2 139.9 +/- 74.1 vs 77.8 +/- 23.3 and t(lag) 95.8 +/- 80.3 vs 32.84 +/- 16.95 min, P0.001 for both comparisons; t-tests). A significant association between hypoglycaemic patients and abnormal values of t1/2 and t(lag) was found (P0.001). Gastric emptying abnormalities were more frequent in hypoglycaemic patients. We suggest gastric emptying tests for diabetic patients with unexplained hypoglycaemic events.

A high prevalence of osteoporosis has been noted in Crohn's disease, but data about fractures are scarce.The relationship between low bone mineral density and the prevalence of vertebral fractures was studied in 271 patients with ileo-caecal Crohn's disease in a large European/Israeli study. One hundred and eighty-one currently steroid-free patients with active Crohn's disease (98 completely steroid-naive) and 90 steroid-dependent patients with inactive or quiescent Crohn's disease were investigated by dual X-ray absorptiometry scan of the lumbar spine, a standardized posterior/anterior and lateral X-ray of the thoracic and lumbar spine, and an assessment of potential risk factors for osteoporosis.Thirty-nine asymptomatic fractures were seen in 25 of 179 steroid-free patients (14.0%; 27 wedge, 12 concavity), and 17 fractures were seen in 13 of 89 steroid-dependent patients (14.6%; 14 wedge, three concavity). The prevalence of fractures in steroid-naive patients was 12.4%. The average bone mineral density, expressed as the T-score, of patients with fractures was not significantly different from that of those without fractures (-0.759 vs. -0.837; P=0.73); 55% of patients with fractures had a normal T-score. The bone mineral density was negatively correlated with lifetime steroids, but not with previous bowel resection or current disease activity. The fracture rate was not correlated with the bone mineral density (P=0.73) or lifetime steroid dose (P=0.83); in women, but not in men, the fracture rate was correlated with age (P=0.009).The lack of correlation between the prevalence of fractures on the one hand and the bone mineral density and lifetime steroid dose on the other necessitates new hypotheses for the pathogenesis of the former.

This study deals with the pattern of estrogen receptors in 52 cases of invasive breast carcinoma by comparing the ligand-binding assays with dextran-coated charcoal (DCC) to an immunoperoxidase assay (IPE) technique in paraffin-embedded material from the same tumor. A modification of the IPE by adding cobalt chloride in the final reaction and counter-staining with eosin instead of hematoxylin was introduced. A significantly high correlation was found between the two compared methods (80.8% positivity by the DCC method and 80% by the IPE method). The correlation was very significant in cases where the immunohistochemical grading was higher than 4 (according to our semi-quantitative evaluation scale of 0-8), and for these cases we suggest the IPE method as highly specific and precise.

Almost 15 years have elapsed since the discussions of the risk of biotechnology began. The tentative principles proposed years ago, that microorganisms were to be contained through the application of proper procedures and practices, and the use of proper facilities and equipment, and that the level of containment was to be matched to the estimated risk, remain applicable and of value today.

The present study deals with the mechanism by which plasmid pCED3 interferes with the growth of Bacillus subtilis. Plasmid pCED3 was constructed from pUB110 and pBR322 and contains the lacZ gene attached to the B. subtilis tms promoter. Plasmid derivatives that contain mutations in the tms promoter were used to examine the effect of promoter strength on cell growth, plasmid stability, the amount of plasmid DNA per cell and the activities of plasmid-encoded enzymes, i.e., beta-galactosidase and kanamycin nucleotidyltransferase (KNT). Efficient lacZ transcription directed from the tms promoter resulted in reduction in growth rate and plasmid stability without an increase in beta-galactosidase activity. The amount of plasmid DNA varied between 6.6 and 12.9 pmol per mg cell protein and showed no clear correlation with the strength of the tms promoter. Transcription from the tms promoter inhibited the expression of the plasmid-encoded kanamycin resistance gene resulting in the reduction of both beta-galactosidase activity and growth rate in the presence of kanamycin. These results suggest that the negative effect on B. subtilis growth exerted by pCED3 results at least partly from a decrease in kanamycin resistance by plasmid-bearing cells.

Will vaccination raise the incidence of autoimmune diseases, what is the impact of increasingly crowded vaccination schedules, the vaccination in age groups and the risk of coincidental temporal association? All these issues are still under debate. However, for the time being, to avoid confusion in the medical community and the media, we have to adhere to guidelines established consensually by experts while ensuring a strict surveillance and reporting possible side effects. Recommendation for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD) based on the currently available evidence and expert opinion were recently formulated by an EULAR task force. Major recommendations for AIIRD include: i) vaccination should ideally be administered during stable disease; ii) influenza vaccination and pneumococcal vaccination should be strongly considered; iii) vaccination can be administered during the use of DMARDs and TNF-inhibitors, but before starting rituximab; iv) live attenuated vaccines should be avoided whenever possible in immunosuppressed patients; v) BCG vaccination is not recommended. (C) 2011 Elsevier B.V. All rights reserved.

Freeze drying and exposure to oxygen of E. coli causes damage to the bacterial cytoplasmic membrane. Freeze-drying itself produces an injury to the transport system for ONPG and potassium, so as to make the membrane leaky to these compounds. This damage is partially repaired upon incubation of the reconstituted bacteria in nutrient medium. When, however, freeze dried bacteria are not held in vacuo before reconstitution, but exposed to oxygen, this damage to the bacterial membrane becomes more extensive and irreversible.

A human adrenocortical adenoma was cultivated in vitro and the morphological characteristics, steroidogenic activity and response to ACTH of the cultured cells were studied over a period of about two months. At first, the morphology of the cultures was similar to that of the original tissue. This structure changed in the course of time and the cells underwent fibroblastoid transformation. Stimulation with ACTH evoked two types of morphological response: a) a short-term response, whereby an extensive but rapidly reversible vacuolization was followed by cell enlargement and granulation, and b) a long-term effect in which the differentiated cell morphology was maintained. The cultures showed a low steroidogenic activity throughout the experiment. ACTH stimulation increased the total 17-hydroxysteroid production up to 10-fold. After ACTH withdrawal the corticosteroid levels declined slowly and about 50% of the maximal activity persisted on the fifth day after ACTH withdrawal.

The damage occurring in freeze-dried bacteria exposed to oxygen is mainly in the bacterial membrane and involves the DNA-initiation complex. This injury occurs in two stages: The primary damage is due to the freeze-drying itself, and is repaired upon reconstitution of bacteria and their subsequent incubation in nutrient broth. The repair process requires protein synthesis. In the next step, the exposure of freezedried bacteria to oxygen, the injury becomes irreversible and the bacteria “die.” The lethal effects of oxygen can be counteracted by either engaging the initiation sites on the membrane (e.g., by colicin E 1 ), or by arresting the activity of the initiation complex. Such arrest occurs in ts-mutants at nonpermissive temperature, or when appropriate mutants are starved of amino acids or thymine. After freeze drying and storage in vacuo , the reconstituted bacteria grow in filaments and synthetize DNA multifocally; they do not form septa and do not divide. After exposure to oxygen of the freeze-dried bacteria the ability to initiate DNA synthesis is lost. It is assumed therefore that oxygen specifically acts on the initiation complex in the bacterial membrane of the freeze-dried bacteria. When an external DNA synthesis control is provided, e.g., by infection with phage the productivity of the freeze-dried bacteria exposed to oxygen is the same as of the lyophilized controls held in vacuo .

The quantitative ratios of RNA:DNA were followed in a developing transplanted fibrosarcoma in C3H mice and in its lung metastases. There was a significant increase in these ratios in developing tumors originating from cell suspensions (P smaller than 0.001) and a single implanted piece (P smaller than 0.05). No significant change was demonstrated in developing fibrosarcoma originating from two pieces of this tumor (P greater than 0.05) which were implanted simultaneously. When comparing the ratios of RNA and DNA of developing lung metastases to the primary tumors, we found a significantly higher ratio in the metastases (P smaller than 0.001). No significant changes in RNA:DNA ratios were demonstrated in normal proliferating tissues either in physiologic hyperplasia or embryo tissue culture (P greater than 0.05).

On the basis of mutual inhibition of uptake with different amino acids in whole cells of Mycobacterium phlei, it was demonstrated that the binding site of proline was different from those of all other amino acids studied. Other groups of amino acids share a common binding site: lysine, histidine, and arginine; valine, leucine, and isoleucine; tryptophan, tyrosine, and phenylalanine; glutamic acid and aspartic acid. The exit and entry processes were studied for proline, glutamine, and glutamic acid. It was observed that in each case the entry and exit processes were mediated by different membrane sites.