Immunological cross-reactivity and neutralisation of European viper venoms with the monospecific Vipera berus antivenom ViperaTAb.

Medically important cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. The mainstay of snakebite therapy is polyclonal antibody therapy, referred to as antivenom. Here we investigate the capability of the monospecific V. berus antivenom, ViperaTAb®, to cross-react with, and neutralise lethality induced by, a variety of European vipers. Using ELISA and immunoblotting, we find that ViperaTAb® antibodies recognise and bind to the majority of toxic components found in the venoms of the Vipera species tested at comparably high levels to those observed with V. berus. Using in vivo pre-clinical efficacy studies, we demonstrate that ViperaTAb® effectively neutralises lethality induced by V. berus, V. aspis, V. ammodytes and V. latastei venoms and at much higher levels than those outlined by regulatory pharmacopoeial guidelines. Notably, venom neutralisation was found to be superior to (V. berus, V. aspis and V. latastei), or as equally effective as (V. ammodytes), the monospecific V. ammodytes "Zagreb antivenom", which has long been successfully used for treating European snake envenomings. This study suggests that ViperaTAb® may be a valuable therapeutic product for treating snakebite by a variety of European vipers found throughout the continent

Small mammal responses to long-term large-scale woodland creation: the influence of local and landscape-level attributes

Habitat loss and fragmentation greatly affect biological diversity. Actions to counteract their negative effects include increasing the quality, amount and connectivity of semi-natural habitats at the landscape scale. However, much of the scientific evidence underpinning landscape restoration comes from studies of habitat loss and fragmentation, and it is unclear whether the ecological principles derived from habitat removal investigations are applicable to habitat creation. In addition, the relative importance of local- (e.g. improving habitat quality) vs. landscape-level (e.g. increasing habitat connectivity) actions to restore species is largely unknown, partly because studying species responses over sufficiently large spatial and temporal scales is challenging. We studied small mammal responses to large scale woodland creation spanning 150 years, and assessed the influence of local- and landscape-level characteristics on three small mammal species of varying woodland affinity. Woodland specialists, generalists and grassland specialists were present in woodlands across a range of ages from 10 to 160 years, demonstrating that these species can quickly colonize newly created woodlands. However, we found evidence that woodlands become gradually better over time for some species. The responses of individual species corresponded to their habitat specificity. A grassland specialist (Microtus agrestis) was influenced only by landscape attributes; a woodland generalist (Apodemus sylvaticus) and specialist (Myodes glareolus) were primarily influenced by local habitat attributes, and partially by landscape characteristics. At the local scale, high structural heterogeneity, large amounts of deadwood and a relatively open understory positively influenced woodland species (both generalists and specialists); livestock grazing had strong negative effects on woodland species abundance. Actions to enhance habitat quality at the patch scale focusing on these attributes would benefit these species. Woodland creation in agricultural landscapes is also likely to benefit larger mammals and birds of prey feeding on small mammals and increase ecosystem processes such as seed dispersal

Recombinant antigens based on toxins A and B of Clostridium difficile that evoke a potent toxin-neutralising immune response

AbstractInfection with the bacterium Clostridium difficile causes symptoms ranging from mild to severe diarrhoea with life-threatening complications and remains a significant burden to healthcare systems throughout the developed world. Two potent cytotoxins, TcdA and TcdB are the prime mediators of the syndrome and rapid neutralisation of these would afford significant benefits in disease management. In the present study, a broad range of non-toxic, recombinant fragments derived from TcdA and TcdB were designed for soluble expression in E. coli and assessed for their capacity to generate a potent toxin-neutralising immune response as assessed by cell-based assays. Significant differences between the efficacies of isolated TcdA and TcdB regions with respect to inducing a neutralising immune response were observed. While the C-terminal repeat regions played the principal role in generating neutralising antibodies to TcdA, in the case of TcdB, the central region domains dominated the neutralising immune response. For both TcdA and TcdB, fragments which comprised domains from both the central and C-terminal repeat region of the toxins were found to induce the most potent neutralising immune responses. Generated antibodies neutralised toxins produced by a range of C. difficile isolates including ribotype 027 and 078 strains. Passive immunisation of hamsters with a combination of antibodies to TcdA and TcdB fragments afforded complete protection from severe CDI induced by a challenge of bacterial spores. The results of the study are discussed with respect to the development of a cost effective immunotherapeutic approach for the management of C. difficile infection

The Iowa Homemaker vol.31, no.2

Healthier Children, Marjorie Miller, page 3 Your Phone Is Rining, Alane Baird, page 4 Dinnertime, Joyce Graber, page 5 Keep Cool, Doris Jean Coxon, page 6 Summer Work Calendar, Nancy Voss, page 7 Here’s an Idea, Darleen Bornschein, Jean McGhie, page 8 Scientific Suds, Beverly Gould, page 10 Eggs With a Soapy Taste, Miriam Newhouse, page 12 What’s New, Constance Cornwell, Harriet LaRue, page 14 Trends, Ruth Anderson, page 1

The Iowa Homemaker vol.31, no.1

Finger or Fork, Doris Jean Coxon, page 3 Learn to Play, Floramae Gates, page 4 What’s Your Beef, Jackie Morrison, page 5 Born to Travel, Ruth Anderson, page 6 Hardships, Colene Ruch, page 7 The O’Bryan Touch, Nancy Voss, page 8 What’s New, Constance Cornwell, Harriet LaRue, page 10 Here’s An Idea, Darleen Bornschein, Jean McGhie, page 12 Alums in the News, Jane Novak, page 15 Trends, Anne Dallager, page 1

Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis

Objective Interleukin-4 (IL-4) can modulate neovascularization. In this study, we used a gene therapy approach to investigate the role of IL-4 in angiogenesis in rat adjuvant-induced arthritis (AIA), a model for rheumatoid arthritis. Methods Rats received an adenovirus producing IL-4 (AxCAIL-4), a control virus without insert, or control vehicle (phosphate buffered saline) intraarticularly before arthritis onset. At peak onset of arthritis, rats were killed. Vascularization was determined in the synovial tissue, and correlations with inflammation were assessed. Ankle homogenates were used in angiogenesis assays in vitro and in vivo, and protein levels of cytokines and growth factors were assessed by enzyme-linked immunosorbent assay. Synovial tissue expression of Αv integrins was determined by immunohistochemistry. Results IL-4 induced a reduction in synovial tissue vessel density, which was paralleled by a decrease in inflammation. AxCAIL-4 joint homogenates significantly ( P < 0.05) inhibited both endothelial cell (EC) migration and tube formation in vitro. Similarly, AxCAIL-4 inhibited capillary sprouting in the rat aortic ring assay, and vessel growth in the in vivo Matrigel plug assay. The angiostatic effect occurred despite high levels of vascular endothelial growth factor (VEGF), and was associated with down-regulation of the proangiogenic cytokines IL-18, CXCL16, and CXCL5 and up-regulation of the angiogenesis inhibitor endostatin. Of interest, AxCAIL-4 also resulted in decreased EC expression of the Αv and Β3 integrin chains. Conclusion In rat AIA, IL-4 reduces synovial tissue vascularization via angiostatic effects, mediates inhibition of angiogenesis via an association with altered pro- and antiangiogenic cytokines, and may inhibit VEGF-mediated angiogenesis and exert its angiostatic role in part via ΑvΒ3 integrin. This knowledge of the specific angiostatic effects of IL-4 may help optimize target-oriented treatment of inflammatory arthritis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55808/1/22034_ftp.pd

In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis

Objective Interleukin-13 (IL-13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL-13 in angiogenesis in vivo, using a rat adjuvant-induced arthritis model of RA. Methods Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL-13 (AxCAIL-13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated. Results AxCAIL-13–treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited ( P < 0.05). Similarly, AxCAIL-13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL-13 gene delivery resulted in up-regulation and association of phosphorylated ERK-1/2 and protein kinase CΑ/ΒII, suggesting a novel pathway in IL-13–mediated angiostasis. The angiostatic effect of AxCAIL-13 was associated with down-regulation of proangiogenic cytokines (IL-18, cytokine-induced neutrophil chemoattractant 1/CXCL1, lipopolysaccharide-induced CXC chemokine/CXCL5) and up-regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL-13 as compared with AxCANI and PBS treatment. Conclusion Our findings support a role for IL-13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56107/1/22823_ftp.pd

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 10(9) cells per L, platelet count at least 100 × 10(9) platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m(2) intravenously on day 1] and fluorouracil [1 g/m(2) per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m(2)] and cisplatin [60 mg/m(2)] intravenously on day 1, and capecitabine [1250 mg/m(2)] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London

Developing a complex intervention for diet and activity behaviour change in obese pregnant women (the UPBEAT trial); assessment of behavioural change and process evaluation in a pilot randomised controlled trial

Background Complex interventions in obese pregnant women should be theoretically based, feasible and shown to demonstrate anticipated behavioural change prior to inception of large randomised controlled trials (RCTs). The aim was to determine if a) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours, and b) to refine the intervention protocol through process evaluation of intervention fidelity. Methods We undertook a pilot RCT of a complex intervention in obese pregnant women, comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake, and increase physical activity. Subjects included 183 obese pregnant women (mean BMI 36.3 kg/m2). Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and questionnaire, at 16+0 to 18+6 and at 27+0 to 28+6 weeks’ gestation in women in control and intervention arms. Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken. The full RCT protocol was undertaken to assess feasibility. Results Compared to women in the control arm, women in the intervention arm had a significant reduction in dietary glycaemic load (33 points, 95% CI −47 to −20), (p < 0.001) and saturated fat intake (−1.6% energy, 95% CI −2.8 to −0. 3) at 28 weeks’ gestation. Objectively measured physical activity did not change. Physical discomfort and sustained barriers to physical activity were common at 28 weeks’ gestation. Process evaluation identified barriers to recruitment, group attendance and compliance, leading to modification of intervention delivery. Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity, and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT. Trial registration Trial Registration Number: ISRCTN8997137

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection