Plant-based immunocontraceptive control of wildlife - "potentials, limitations, and possums"

Possums (Trichosurus vulpecula), originally introduced from Australia, are spread over 90% of New Zealand and cause major economic and environmental damage. Immunocontraception has been suggested as a humane means to control them. Marsupial-specific reproductive antigens expressed at high levels in edible transgenic plant tissue might provide a safe, effective, and cheap oral delivery bait for immuno-contraceptive control. As proof of concept, female possums vaccinated with immunocontraceptive antigens showed reduced fertility, and possums fed with potato-expressed heat labile toxin-B (LT-B) had mucosal and systemic immune responses to the antigen. This demonstrated that immunocontraception was effective in possums and that oral delivery in edible plant material might be possible. Nuclear transformation with reporter genes showed that transgenic carrot roots accumulate high levels of foreign protein in edible tissues, indicating their potential as a delivery vector. However, prior to attempts at large scale production, more effective immunocontraceptive antigen-adjuvant formulations are probably required before plant-based immunocontraception can become a major tool for immunocontraceptive control of overabundant vertebrate pests. (c) 2004 Elsevier Ltd. All rights reserved.

Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency

Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (~50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (~60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to ~40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.

Physiological and haematological findings and clinical observations in a model of acute systemic anaphylaxis in Dirofilaria immitis-sensitised cats

Objective This study aims to understand the pathophysiology of anaphylaxis in Dirofflaria immitis-sensitised cats by analysing objective physiological and haematological measurements after challenge. Design Nineteen healthy D immitis-naive cats were sensitised using weekly injections of aluminium hydroxide-adjuvanted D immitis antigen, administered subcutaneously over 6 weeks. After sensitisation, cats (n = 16) were anaesthetised and challenged with intravenous D immitis antigen. A control group (n = 3) was sham-challenged using intravenous sterile 0.9% saline. Systolic blood pressure (measured non-invasively/indirectly), respiratory rate, degree of dyspnoea, blood 0, saturation, expired CO2, and heart rate and were measured immediately before and at 10 to 15 min intervals after challenge until terminal apnoea occurred or euthanasia at 140 mins post-challenge. Blood was collected for complete blood count immediately before and at 10, 20 and 35 mins after challenge. Clinical observations were recorded as they occurred. Results Antigen-challenged cats were divided into two groups: acute (apnoea occurred within 25 mins of challenge) and subacute (breathing at 25 mins after challenge). In both groups, the degree of dyspnoea increased and blood O-2 saturation and blood pressure decreased. Respiratory rate increased in the subacute group. Expired CO2 decreased in both Ag-challenged and control groups. Haematocrit increased in the subacute group. Neutrophil count decreased in the acute group and platelet count decreased in the subacute group. Eosinophil count decreased in the subacute and control groups. Sustained dyspnoea and gastrointestinal signs were the most common clinical manifestations of anaphylaxis in the antigen-challenged cats. Conclusions Intravenous challenge with D immitis antigen in sensitised cats results in dyspnoea, hypoxaemia and systemic hypotension accompanied by haemoconcentration.

The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against ubiquitous antigens, especially nuclear components. Evidence makes it clear that the development of these autoantibodies is an antigen-driven process and that immune complexes involving DNA-containing antigens play a key role in the disease process. In rodents, DNase I is the major endonuclease present in saliva, urine and plasma, where it catalyses the hydrolysis of DNA, and impaired DNase function has been implicated in the pathogenesis of SLE. In this study we have evaluated the effects of transgenic overexpression of murine DNase I endonucleases in vivo in a mouse model of lupus. We generated transgenic mice having T-cells that express either wild-type DNase I (wt. DNase I) or a mutant DNase I ( ash. DNase I), engineered for three new properties - resistance to inhibition by G-actin, resistance to inhibition by physiological saline and hyperactivity compared to wild type. By crossing these transgenic mice with a murine strain that develops SLE we found that, compared to control nontransgenic littermates or wt. DNase I transgenic mice, the ash. DNase I mutant provided significant protection from the development of anti-single-stranded DNA and anti-histone antibodies, but not of renal disease. In summary, this is the first study in vivo to directly test the effects of long-term increased expression of DNase I on the development of SLE. Our results are in line with previous reports on the possible clinical benefits of recombinant DNase I treatment in SLE, and extend them further to the use of engineered DNase I variants with increased activity and resistance to physiological inhibitors.

8-Hydroxydeoxyguanosine. A marker of oxidative DNA damage in systemic lupus erythematosus

8-Hydroxydeoxyguanosine (80HDG) is a specific marker of oxidative damage to DNA. We have observed that patients with SLE (systemic lupus erythematosus), have undetectable levels of urinary 80HDG by HPLC. Further analysis by GC-MS confirmed that levels of 80HDG in SLE urine were 10(3)-fold lower than in an age- and sex-matched control group. Experiments utilising cultures of SLE and normal lymphocytes exposed to H2O2 confirmed the impaired ability of SLE lymphocytes to repair 80HDG. We subsequently observed in SLE patients that 80HDG had accumulated in low molecular weight DNA associated with circulating immune complexes. We suggest that oxygen radicals may induce pathology in SLE by maintaining the presence of an antigenic form of DNA in the circulation.

Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma

PURPOSE. To assess the level of plasma glutathione in patients with untreated primary open-angle glaucoma. METHODS. Twenty-one patients with newly diagnosed primary open-angle glaucoma and 34 age- and gender-matched control subjects were subjected to a blood analysis to detect the level of circulating glutathione in its reduced and oxidized forms. The effect of age, gender, and systemic blood pressure on circulating glutathione levels was also analyzed. RESULTS. Age had a negative effect on the level of both reduced and total glutathione (P = 0.002, r = -0.52 and P = 0.002, r = -0.52, respectively) in control subjects but not in patients with glaucoma (P > 0.05, r = 0.27, and P > 0.05, r = 0.22, respectively). In the control group, men demonstrated higher levels of both reduced and total glutathione than did women (P = 0.024 and P = 0.032, respectively). After correction for age and gender influences on blood glutathione levels, patients with glaucoma exhibited significantly lower levels of reduced and total glutathione than did control subjects (P = 0.010, F = 7.24 and P = 0.006, F = 8.38, respectively). No differences between study groups were observed in either oxidized glutathione levels or redox index (P > 0.05, F = 0.50; and P > 0.05, F = 0.30, respectively). CONCLUSIONS. Patients with glaucoma exhibit low levels of circulating glutathione, suggesting a general compromise of the antioxidative defense. Copyright © Association for Research in Vision and Ophthalmology.

Improving the description of the retinal vasculature and patient history taking for monitoring systemic hypertension

Systemic hypertension is an important public health concern. If optometrists are to perform a more active role in the detection and monitoring of high blood pressure (BP), there is a need to improve the consistency of describing the retinal vasculature and to assess patient's ability to correctly report the diagnosis of hypertension, its control and medication. One hundred and one patients aged >40 years were dilated and had fundus photography performed. BP was measured and a self-reported history of general health and current medication was compared with the records of their general practitioner (GP). The status of the retinal vasculature was quantified using a numeric scale by five clinicians and this was compared to the same evaluation performed with the aid of a basic pictorial grading scale. Image analysis was used to objectively measure the artery-to-vein (A/V) ratio and arterial reflex. Arteriolar tortuosity and calibre changes were found to be the most sensitive retinal signs of high BP. Using the grading scale to describe the retinal vasculature significantly improved inter- and intra-observer repeatability. Almost half the patients examined were on medication for high BP or cardiovascular disease. Patients' ability to give their complete medical history was poor, as was their ability to recall what medication they had been prescribed. GPs indicated it was useful to receive details of their patient's BP when it was >140/90 mmHg. The use of improved description of the retinal vasculature and stronger links between optometrists and GPs may enhance future patient care. © 2001 The College of Optometrists. Published by Elsevier Science Ltd. All rights reserved.

Abnormal systemic and ocular vascular response to temperature provocation in primary open-angle glaucoma patients:a case for autonomic failure?

PURPOSE. To assess systemic and ocular vascular reactivity in response to warm and cold provocation in untreated patients with primary open-angle glaucoma and normal control subjects. METHODS. Twenty-four patients with primary open-angle glaucoma and 22 normal control subjects were subjected to a modified cold pressor test involving immersion of the right hand in 40°C warm water followed by 4°C cold water exposure, and finger and ocular blood flow were assessed by means of peripheral laser Doppler flowmetry and retinal flowmetry, respectively. Finger and body temperature as well as intraocular pressure, systemic blood pressure, systemic pulse pressure, heart rate, and ocular perfusion pressure were also monitored. RESULTS. The patients with glaucoma demonstrated an increase in diastolic blood pressure (P = 0.023), heart rate (P = 0.010), and mean ocular perfusion pressure (P = 0.039) during immersion of the tested hand in 40°C water. During cold provocation, the patients demonstrated a significant decrease in finger (P = 0.0003) and ocular blood flow (the parameter velocity measured at the temporal neuroretinal rim area; P = 0.021). Normal subjects did not demonstrate any blood flow or finger temperature changes during immersion of the tested hand in 40°C water (P > 0.05); however, they exhibited increases in systolic blood pressure (P = 0.034) and pulse pressure (P = 0.0009) and a decrease in finger blood flow (P = 0.0001) during cold provocation. In normal subjects, the ocular blood flow was unchanged during high- and low-temperature challenge. CONCLUSIONS. Cold provocation elicits a different blood pressure, and ocular blood flow response in patients with primary open-angle glaucoma compared with control subjects. These findings suggest a systemic autonomic failure and ocular vascular dysregulation in POAG patients.

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses.

Systemic inflammatory impact of periodontitis on acute coronary syndrome

Aim: A causative relationship between acute coronary syndrome (ACS) and periodontitis has yet to be defined. The aim of this study was to assess differences in levels of serum cytokines between individuals with or without ACS or periodontal comorbidity. Material and Methods: In a case–control study, individuals with ACS (78 individuals, 10.3% females) and matching healthy controls (78 individuals, 28.2% females) were included. Medical and dental examinations were performed to diagnose ACS and periodontitis. Serum levels of cytokines were assessed, using Luminex technology. Results: A diagnosis of periodontitis in the ACS and control group was diagnosed in 52.6% and 12.8% of the individuals, respectively. The unadjusted odds-ratio that individuals with ACS also had periodontitis was 7.5 (95% CI: 3.4, 16.8, p 

Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

Background

It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
Objectives

To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
Search methods

We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Selection criteria

Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis

Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Main results

Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I2= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I2 = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I2 = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Authors' conclusions

Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

Procalcitonin Biomarker Kinetics to Predict Multiorgan Dysfunction Syndrome in Children With Sepsis and Systemic Inflammatory Response Syndrome

Background: Procalcitonin (PCT) kinetics is a good prognosis marker in infectious diseases, but few studies of children sepsis have been performed. Objectives: The aim of our study was to examine kinetics of procalcitonin, to evaluate its relationship with severity and to analyze its usefulness in the prediction of multiorgan dysfunction syndrome (MODS). Patients and Methods: Prospective observational study in an 8-bed pediatric intensive care unit of a university hospital. Sixty-two children aged 0-19 years with systemic inflammatory response syndrome or septic states. The degree of severity was evaluated according pediatric logistic organ dysfunction (PELOD) score. Blood tests to determine levels of PCT were taken if the patients had the criteria of systemic inflammatory response syndrome or sepsis. The serum to determine levels of PCT in control group has been taken from patients undergoing elective surgery. Results: Higher values of PCT were identified in patients with PELOD score 12 and more compared to those with PELOD < 12 (P = 0.016). Similarly, higher PCT values were found in patients who developed MODS in contrast to those without MODS (P = 0.011). According to ROC analysis cut-off value of 4.05 ng/mL was found to best discriminate patients with PELOD < 12 and PELOD ≥ 12 with AUC = 0.675 (P = 0.035). Effect of procalcitonin levels on mortality was not demonstrated. Conclusions: Levels of procalcitonin from day 1 to day 5 are related to the severity and multiorgan dysfunction syndrome in children.

Inhibition of nitro-oxidative stress attenuates pulmonary and systemic injury induced by high-tidal volume mechanical ventilation

Mechanisms contributing to pulmonary and systemic injury induced by high tidal volume (VT) mechanical ventilation are not well known. We tested the hypothesis that increased peroxynitrite formation is involved in organ injury and dysfunction induced by mechanical ventilation. Male Sprague-Dawley rats were subject to low- (VT, 9 mL/kg; positive end-expiratory pressure, 5 cmH2O) or high- (VT, 25 mL/kg; positive end-expiratory pressure, 0 cmH2O) VT mechanical ventilation for 120 min, and received 1 of 3 treatments: 3-aminobenzamide (3-AB, 10 mg/kg, intravenous, a poly adenosine diphosphate ribose polymerase [PARP] inhibitor), or the metalloporphyrin manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, 5 mg/kg intravenous, a peroxynitrite scavenger), or no treatment (control group), 30 min before starting the mechanical ventilation protocol (n = 8 per group, 6 treatment groups). We measured mean arterial pressure, peak inspiratory airway pressure, blood chemistry, and gas exchange. Oxidation (fluorescence for oxidized dihydroethidium), protein nitration (immunofluorescence and Western blot for 3-nitrotyrosine), PARP protein (Western blot) and gene expression of the nitric oxide (NO) synthase (NOS) isoforms (quantitative real-time reverse transcription polymerase chain reaction) were measured in lung and vascular tissue. Lung injury was quantified by light microscopy. High-VT mechanical ventilation was associated with hypotension, increased peak inspiratory airway pressure, worsened oxygenation; oxidation and protein nitration in lung and aortic tissue; increased PARP protein in lung; up-regulation of NOS isoforms in lung tissue; signs of diffuse alveolar damage at histological examination. Treatment with 3AB or MnTMPyP attenuated the high-VT mechanical ventilation-induced changes in pulmonary and cardiovascular function; down-regulated the expression of NOS1, NOS2, and NOS3; decreased oxidation and nitration in lung and aortic tissue; and attenuated histological changes. Increased peroxynitrite formation is involved in mechanical ventilation-induced pulmonary and vascular dysfunction.

Review of the Community Residential Care Facilities Program, Department of Health and Environmental Control

This review was predicated on a credible complaint alleging substantial health and safety deficiencies in the care of a resident placed in a Community Residential Care Facility (CRCF) in Kershaw County, South Carolina. Initial investigation with subject matter experts, non-profit advocacy groups, and CRCF inspection reports revealed this single incident might be a symptom of systemic health and safety deficiencies throughout DHEC’s CRCF Program, which regulates 471 CRCFs with the approximately 17,000 vulnerable clients, primarily elderly and disabled. This review’s scope and objectives were: Assess the risk of a vulnerable population of elderly and disabled citizens residing in CRCFs living in unsatisfactory health and safety conditions; Evaluate DHEC’s CRCF Program inspection process capabilities to identify and address CRCFs with unsatisfactory health and safety living conditions; Recommend opportunities to improve the CRCF Program.