Characterisation of two snake toxin-targeting human monoclonal immunoglobulin G antibodies expressed in tobacco plants.

Current snakebite antivenoms are based on polyclonal animal-derived antibodies, which can neutralize snake venom toxins in envenomed victims, but which are also associated with adverse reactions. Therefore, several efforts within antivenom research aim to explore the utility of recombinant monoclonal antibodies, such as human immunoglobulin G (IgG) antibodies, which are routinely used in the clinic for other indications. In this study, the feasibility of using tobacco plants as bioreactors for expressing full-length human monoclonal IgG antibodies against snake toxins was investigated. We show that the plant-produced antibodies perform similarly to their mammalian cell-expressed equivalents in terms of in vitro antigen binding. Complete neutralization was achieved by both the plant and mammalian cell-produced anti-α-cobratoxin antibody. The feasibility of using plant-based expression systems may potentially make it easier for laboratories in resource-poor settings to work with human monoclonal IgG antibodies.

Cross-reactivity trends when selecting scFv antibodies against snake toxins using a phage display-based cross-panning strategy.

Antibodies with cross-reactive binding and broad toxin-neutralizing capabilities are advantageous for treating indications such as infectious diseases and animal envenomings. Such antibodies have been successfully selected against closely related antigens using phage display technology. However, the mechanisms driving antibody cross-reactivity typically remain to be elucidated. Therefore, we sought to explore how a previously reported phage display-based cross-panning strategy drives the selection of cross-reactive antibodies using seven different snake toxins belonging to three protein (sub-)families: phospholipases A2, long-chain α-neurotoxins, and short-chain α-neurotoxins. We showcase how cross-panning can increase the chances of discovering cross-reactive single-chain variable fragments (scFvs) from phage display campaigns. Further, we find that the feasibility of discovering cross-reactive antibodies using cross-panning cannot easily be predicted by analyzing the sequence, structural, or surface similarity of the antigens alone. However, when antigens share the (exact) same functions, this seems to increase the chances of selecting cross-reactive antibodies, which may possibly be due to the existence of structurally similar motifs on the antigens.

Role of dietary fibre in older adults with asymptomatic (AS) or symptomatic uncomplicated diverticular disease (SUDD): Systematic review and meta-analysis.

Dietary fibre and probiotics may play a role in the management of diverticular disease. This systematic review synthesises the evidence on the effects of dietary fibre modifications, with or without the use of probiotics, on the incidence in older adults of asymptomatic (AS) or symptomatic uncomplicated diverticular disease (SUDD), as well as on gastrointestinal function and symptoms. Five electronic databases were searched for studies through to December 2018. The body of evidence was appraised using the Cochrane Risk of Bias tool and GRADE. Nine studies were included, with mean sample ages ranging from 57 to 70 years, and three meta-analyses were performed. Only one study, with high risk of bias, measured the effect of dietary fibre on the incidence of diverticulitis. Dietary fibre supplementation improved stool weight (MD: 42 g/day, P < 0.00001; GRADE level of evidence: low), but had no significant effect on gastrointestinal symptoms (SMD: -0.13, P = 0.16; GRADE level of evidence: low) or stool transit time (MD: -3.70, P = 0.32 GRADE level of evidence: low). There was "very low" confidence for the body of evidence supporting symbiotics for AS or SUDD. A high dietary fibre intake, in line with dietary guidelines, may improve gastrointestinal function and is recommended in patients with AS or SUDD. Dietary fibre supplementation should be considered on an individualised basis to improve bowel function, while any recommendation on symbiotic supplements requires further well-designed research. Future studies should also measure the impact on the incidence of diverticulitis.

Effects of Exercise Training and IL-6 Receptor Blockade on Gastric Emptying and GLP-1 Secretion in Obese Humans: Secondary Analyses From a Double Blind Randomized Clinical Trial.

BACKGROUND: Interleukin-6 (IL-6) is released from skeletal muscle during exercise and systemic IL-6 levels therefore increase acutely in response to a single bout of exercise. We recently showed that an acute increase in IL-6 delayed gastric emptying rate and improved postprandial glycemia. Here we investigate whether repeated increases in IL-6, induced by exercise training, influence gastric emptying rate and moreover if IL-6 is required for exercise-induced adaptations in glycemic control including secretion of glucagon and glucagon-like peptide-1 (GLP-1). METHODS: A total of 52 abdominally obese non-diabetic men and women were randomly assigned into four groups performing 12 weeks of endurance exercise or no exercise with or without IL-6 receptor blockade (tocilizumab). The primary endpoint was change in gastric emptying rate in response to the intervention and other endpoints included changes in glycemic control, glucagon, and GLP-1 secretion. RESULTS: There was no change in gastric emptying rate in any of the four groups following the intervention and comparing differences in change between groups also revealed no difference. Postprandial glucose remained unchanged in all groups but the exercise + tocilizumab group, which improved postprandial glucose in response to the intervention. The area under the curve for meal-stimulated glucagon, active and total GLP-1 increased in response to IL-6 receptor blockade, this effect was independent of exercise. CONCLUSION: Exercise training and long-term IL-6 receptor blockade did not change gastric emptying rates in obese humans. IL-6 receptor blockade increased glucagon and GLP-1 secretion and implicate IL-6 in the regulation of the human alpha and L cells.

Effect of Aerobic and Resistance Exercise on Cardiac Adipose Tissues: Secondary Analyses From a Randomized Clinical Trial.

Importance: Epicardial and pericardial adipose tissues are emerging as important risk factors for cardiovascular disease, and there is a growing interest in discovering strategies to reduce the accumulation of fat in these depots. Objective: To investigate whether a 12-week endurance or resistance training intervention regulates epicardial and pericardial adipose tissue mass. Design, Setting, and Participants: Secondary analysis of a randomized, assessor-blinded clinical trial initiated on August 2016 and completed April 2018. This single-center, community-based study included 50 physically inactive participants with abdominal obesity. Interventions: Participants were randomized to a supervised high-intensity interval endurance training (3 times a week for 45 minutes), resistance training (3 times a week for 45 minutes), or no exercise (control group). Main Outcomes and Measures: Change in epicardial and pericardial adipose tissue mass assessed by magnetic resonance imaging, based on a prespecified secondary analysis plan including 3 of 5 parallel groups. Results: Of 50 participants (mean [SD] age, 41 [14] years, 10 men [26%]; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32 [5]), 39 [78%] completed the study. Endurance training and resistance training reduced epicardial adipose tissue mass by 32% (95% CI, 10%-53%) and 24% (95% CI, 1%-46%), respectively, compared with the no exercise control group (56% [95% CI, 24%-88%]; P = .001 and 48% [95% CI, 15%-81%]; P < .001, respectively). While there was a nonsignificant reduction in pericardial adipose tissue mass after endurance training (11% [95% CI, -5% to 27%]; P = .17), resistance training significantly reduced pericardial adipose tissue mass by 31% (95% CI, 16%-47%; P < .001) when compared with the no exercise control group. Compared with the no exercise control group, there was an increase in left ventricular mass by endurance (20 g [95% CI, 11%-30%]; P < .001) and resistance training (18 g [95% CI, 8%-28%]; P < .001). Other cardiometabolic outcomes remained unchanged after the 12-week trial period. Conclusions and Relevance: In individuals with abdominal obesity, both endurance and resistance training reduced epicardial adipose tissue mass, while only resistance training reduced pericardial adipose tissue mass. These data highlight the potential preventive importance of different exercise modalities as means to reduce cardiac fat in individuals with abdominal obesity. Trial Registration: ClinicalTrials.gov identifier: NCT02901496.

Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial.

Visceral adipose tissue is harmful to metabolic health. Exercise training reduces visceral adipose tissue mass, but the underlying mechanisms are not known. Interleukin-6 (IL-6) stimulates lipolysis and is released from skeletal muscle during exercise. We hypothesized that exercise-induced reductions in visceral adipose tissue mass are mediated by IL-6. In this randomized placebo-controlled trial, we assigned abdominally obese adults to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either bicycle exercise or no exercise. While exercise reduced visceral adipose tissue mass, this effect of exercise was abolished in the presence of IL-6 blockade. Changes in body weight and total adipose tissue mass showed similar tendencies, whereas lean body mass did not differ between groups. Also, IL-6 blockade increased cholesterol levels, an effect not reversed by exercise. Thus, IL-6 is required for exercise to reduce visceral adipose tissue mass and emphasizes a potentially important metabolic consequence of IL-6 blockade.

Evidence for Dietary Fibre Modification in the Recovery and Prevention of Reoccurrence of Acute, Uncomplicated Diverticulitis: A Systematic Literature Review.

In practice, nutrition recommendations vary widely for inpatient and discharge management of acute, uncomplicated diverticulitis. This systematic review aims to review the evidence and develop recommendations for dietary fibre modifications, either alone or alongside probiotics or antibiotics, versus any comparator in adults in any setting with or recently recovered from acute, uncomplicated diverticulitis. Intervention and observational studies in any language were located using four databases until March 2017. The Cochrane Risk of Bias tool and GRADE were used to evaluate the overall quality of the evidence and to develop recommendations. Eight studies were included. There was "very low" quality evidence for comparing a liberalised and restricted fibre diet for inpatient management to improve hospital length of stay, recovery, gastrointestinal symptoms and reoccurrence. There was "very low" quality of evidence for using a high dietary fibre diet as opposed to a standard or low dietary fibre diet following resolution of an acute episode, to improve reoccurrence and gastrointestinal symptoms. The results of this systematic review and GRADE assessment conditionally recommend the use of liberalised diets as opposed to dietary restrictions for adults with acute, uncomplicated diverticulitis. It also strongly recommends a high dietary fibre diet aligning with dietary guidelines, with or without dietary fibre supplementation, after the acute episode has resolved.