C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis.

BACKGROUND: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent ß-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of ß-cell function and metabolic outcomes in new-onset type 1 diabetes. METHODS: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. FINDINGS: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. INTERPRETATION: Interventions that preserve ß-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. FUNDING: JDRF and Diabetes UK.

New Approaches to Manage Asian Soybean Rust (Phakopsora pachyrhizi) Using Trichoderma spp. or Their Antifungal Secondary Metabolites.

Attempts have been made to determine the in vitro and in planta suppressive potential of particular Trichoderma strains (T16 and T23) and their secondary metabolites (SMs) against Asian soybean rust (ASR) incited by Phakopsora pachyrhizi. Aside from the previously identified SMs 6-pentyl-α-pyrone (6PAP) and viridiofungin A (VFA), the chemical structures of harzianic acid (HA), iso-harzianic acid (iso-HA), and harzianolide (HZL) were characterized in this study. Our results indicate that exposure of urediospores to 200 ppm 6PAP completely inhibits germination. A slightly higher dosage (250 ppm) of HZL and VFA reduces germination by 53.7% and 44%, respectively. Germ tube elongation seems more sensitive to 6PAP than urediospore germination. On detached leaves, application of conidia of T16 and T23 results in 81.4% and 74.3% protection, respectively. Likewise, 200 ppm 6PAP recorded the highest ASR suppression (98%), followed by HZL (78%) and HA (69%). Treatment of undetached leaves with 6PAP, HA, or HZL reduces ASR severity by 84.2%, 65.8%, and 50.4%, respectively. Disease reduction on the next, untreated trifoliate by T23 (53%), T16 (41%), HZL (42%), and 6PAP (32%) suggests a translocation or systemic activity of the SMs and their producers. To our knowledge, this study provides the first proof for controlling ASR using antifungal SMs of Trichoderma. Our findings strongly recommend the integration of these innovative metabolites, particularly 6PAP and/or their producers in ASR management strategies.

Role of Benzoic Acid and Lettucenin A in the Defense Response of Lettuce against Soil-Borne Pathogens.

Soil-borne pathogens can severely limit plant productivity. Induced defense responses are plant strategies to counteract pathogen-related damage and yield loss. In this study, we hypothesized that benzoic acid and lettucenin A are involved as defense compounds against Rhizoctonia solani and Olpidium virulentus in lettuce. To address this hypothesis, we conducted growth chamber experiments using hydroponics, peat culture substrate and soil culture in pots and minirhizotrons. Benzoic acid was identified as root exudate released from lettuce plants upon pathogen infection, with pre-accumulation of benzoic acid esters in the root tissue. The amounts were sufficient to inhibit hyphal growth of R. solani in vitro (30%), to mitigate growth retardation (51%) and damage of fine roots (130%) in lettuce plants caused by R. solani, but were not able to overcome plant growth suppression induced by Olpidium infection. Additionally, lettucenin A was identified as major phytoalexin, with local accumulation in affected plant tissues upon infection with pathogens or chemical elicitation (CuSO4) and detected in trace amounts in root exudates. The results suggest a two-stage defense mechanism with pathogen-induced benzoic acid exudation initially located in the rhizosphere followed by accumulation of lettucenin A locally restricted to affected root and leaf tissues.

Brachialactone isomers and derivatives of Brachiaria humidicola reveal contrasting nitrification inhibiting activity.

Biological Nitrification Inhibition (BNI) of Brachiaria humidicola has been mainly attributed to the root-exuded fusicoccane-type diterpene brachialactone. We hypothesized, however, that according to the high diversity of fusicoccanes described for plants and microorganisms, BNI of B. humidicola is caused by an assemblage of bioactive fusicoccanes. B. humidicola root exudates were collected hydroponically and compounds isolated by semi-preparative HPLC. Chemical structures were revealed by spectroscopic techniques, including HRMS as well as 1D and 2D NMR. Nitrification inhibiting (NI) potential of isolated compounds was evaluated by a Nitrosomonas europaea based bioassay. Besides the previously described brachialactone (1), root exudates contained 3-epi-brachialactone (2), the C3-epimer of 1 (m/z 334), as well as 16-hydroxy-3-epi-brachialactone (3) with an additional hydroxyl group at C16 (m/z 350) and 3,18-epoxy-9-hydroxy-4,7-seco-brachialactone (4), which is a ring opened brachialactone derivative with a 3,18 epoxide ring and a hydroxyl group at C9 (m/z 332). The 3-epi-brachialactone (2) showed highest NI activity (ED50 ~ 20 µg mL-1, ED80 ~ 40 µg mL-1), followed by compound 4 with intermediate (ED50 ~ 40 µg mL-1), brachialactone (1) with low and compound 3 without activity. In coherence with previous reports on fusicoccanes, stereochemistry at C3 was of high relevance for the biological activity (NI potential) of brachialactones.

Synergisms of Microbial Consortia, N Forms, and Micronutrients Alleviate Oxidative Damage and Stimulate Hormonal Cold Stress Adaptations in Maize.

AIMS: Low soil temperature in spring is a major constraint for the cultivation of tropical crops in temperate climates. This study aims at the exploitation of synergistic interactions of micronutrients, consortia of plant growth-promoting microorganisms and N forms as cold-stress protectants. METHODS: Maize seedlings were exposed for two weeks to low root zone temperatures at 8-14°C under controlled conditions on a silty clay-loam soil (pH 6.9) collected from a maize field cultivation site. A pre-selection trial with fungal and bacterial PGPM strains revealed superior cold-protective performance for a microbial consortium of Trichoderma harzianum OMG16 and Bacillus spp. with Zn/Mn supplementation (CombiA+), particularly in combination with N-ammonium as a starting point for the characterization of the underlying physiological and molecular mechanisms. RESULTS: In nitrate-treated plants, the cold stress treatment increased oxidative leaf damage by 133% and reduced the shoot biomass by 25%, related with reduced acquisition of phosphate (P), zinc (Zn) and manganese (Mn). The supplying of N as ammonium improved the Zn and Mn nutritional status and increased the ABA shoot concentration by 33%, as well as moderately increased detoxification of reactive oxygen species (ROS). Moreover, use of N as ammonium also increased the root auxin (IAA) concentration (+76%), with increased expression of auxin-responsive genes, involved in IAA synthesis (ZmTSA), transport (ZmPIN1a), and perception (ZmARF12). Additional inoculation with the microbial consortium promoted root colonization with the inoculant strain T. harzianum OMG16 in combination with ammonium fertilization (+140%). An increased ABA/cytokinin ratio and increased concentrations of jasmonic (JA) and salicylic acids (SA) were related to a further increase in enzymatic and non-enzymatic ROS detoxification. Additional supplementation with Zn and Mn further increased shoot IAA, root length and total antioxidants, resulting in the highest shoot biomass production and the lowest leaf damage by oxidative chemical species. CONCLUSION: Our results suggest the mitigation of cold stress and reduction of stress priming effects on maize plants due to improved ROS detoxification and induction of hormonal stress adaptations relying on the strategic combination of stress-protective nutrients with selected microbial inoculants.

Impact of Long-Term Organic and Mineral Fertilization on Rhizosphere Metabolites, Root-Microbial Interactions and Plant Health of Lettuce.

Fertilization management can affect plant performance and soil microbiota, involving still poorly understood rhizosphere interactions. We hypothesized that fertilization practice exerts specific effects on rhizodeposition with consequences for recruitment of rhizosphere microbiota and plant performance. To address this hypothesis, we conducted a minirhizotron experiment using lettuce as model plant and field soils with contrasting properties from two long-term field experiments (HUB-LTE: loamy sand, DOK-LTE: silty loam) with organic and mineral fertilization history. Increased relative abundance of plant-beneficial arbuscular mycorrhizal fungi and fungal pathotrophs were characteristic of the rhizospheres in the organically managed soils (HU-org; BIODYN2). Accordingly, defense-related genes were systemically expressed in shoot tissues of the respective plants. As a site-specific effect, high relative occurrence of the fungal lettuce pathogen Olpidium sp. (76-90%) was recorded in the rhizosphere, both under long-term organic and mineral fertilization at the DOK-LTE site, likely supporting Olpidium infection due to a lower water drainage potential compared to the sandy HUB-LTE soils. However, plant growth depressions and Olpidium infection were exclusively recorded in the BIODYN2 soil with organic fertilization history. This was associated with a drastic (87-97%) reduction in rhizosphere abundance of potentially plant-beneficial microbiota (Pseudomonadaceae, Mortierella elongata) and reduced concentrations of the antifungal root exudate benzoate, known to be increased in presence of Pseudomonas spp. In contrast, high relative abundance of Pseudomonadaceae (Gammaproteobacteria) in the rhizosphere of plants grown in soils with long-term mineral fertilization (61-74%) coincided with high rhizosphere concentrations of chemotactic dicarboxylates (succinate, malate) and a high C (sugar)/N (amino acid) ratio, known to support the growth of Gammaproteobacteria. This was related with generally lower systemic expression of plant defense genes as compared with organic fertilization history. Our results suggest a complex network of belowground interactions among root exudates, site-specific factors and rhizosphere microbiota, modulating the impact of fertilization management with consequences for plant health and performance.

Silicon Improves Chilling Tolerance During Early Growth of Maize by Effects on Micronutrient Homeostasis and Hormonal Balances.

Low soil temperature in spring is a major constraint for the cultivation of tropical and subtropical crops in temperate climates, associated with inhibition of root growth and activity, affecting early growth and frequently plant performance and final yield. This study was initiated to investigate the physiological base of cold-protective effects induced by supplementation with silicon (Si), widely recommended as a stress-protective mineral nutrient. Maize was used as a cold-sensitive model plant, exposed to chilling stress and low root-zone temperature (RZT) during early growth in a lab to field approach. In a pot experiment, 2-weeks exposure of maize seedlings to low RZT of 12-14°C, induced leaf chlorosis and necrosis, inhibition of shoot and root growth and micronutrient limitation (particularly Zn and Mn). These phenotypes were mitigated by seed treatments with the respective micronutrients, but surprisingly, also by Si application. Both, silicon and micronutrient treatments were associated with increased activity of superoxide dismutase in shoot and roots (as a key enzyme for detoxification of reactive oxygen species, depending on Zn and Mn as cofactors), increased tissue concentrations of phenolics, proline, and antioxidants, but reduced levels of H2O2. These findings suggest that mitigation of oxidative stress is a major effect of Zn, Mn, and Si applied as cold stress protectants. In a soil-free culture system without external nutrient supply, Si significantly reduced large leaching losses of Zn and Mn from germinating seeds exposed to low-temperature stress. Silicon also increased the translocation of micronutrient seed reserves to the growing seedling, especially the Zn shoot translocation. In later stages of seedling development (10 days after sowing), cold stress reduced the root and shoot contents of important hormonal growth regulators (indole acetic acid, gibberellic acid, zeatin). Silicon restored the hormonal balances to a level comparable with non-stressed plants and stimulated the production of hormones involved in stress adaptation (abscisic, salicylic, and jasmonic acids). Beneficial effects of Si seed treatments on seedling establishment and the nutritional status of Zn and Mn were also measured for a field-grown silage maize, exposed to chilling stress by early sowing. This translated into increased final biomass yield.

Inappropriate use of proton pump inhibitors among medical inpatients: a questionnaire-based observational study.

OBJECTIVES: To evaluate the appropriateness of proton pump inhibitor (PPI) prescribing by conducting an audit of medical inpatients against recommended guidelines. DESIGN: Questionnaire-based study. All medical wards were audited and different information was documented by patients' medical records review (both hospital visit notes and general practitioner's letters) and short interview, where we asked them to name the clinical reason for using PPI. SETTING: This study was carried out in the setting of a regional hospital (537-bed, secondary care referral centre) in Ireland. PARTICIPANTS: The study participants were all consecutive medical patients admitted to the medical wards at Waterford Regional Hospital, Waterford. MAIN OUTCOME MEASURES: The appropriateness of PPI usage in our regional hospital by assessing the level of its prescribing against published guidelines (NICE, 2000). RESULTS: During the audit period, 205 consecutive medical inpatients were assessed. Seventy-nine percent (162 out of 205) of the studied patients were found to be using PPI. For 45% (n = 73) of patients, there was no documentation of valid indication for being on PPI. Overall, 64% of patients were prescribed PPI by hospital doctors, either during their current or previous admissions. We noted that 31% (n = 51) of patients were taking PPI for ≥2 years and another 25% of patients were using PPI for about one year. Only 12% (n = 20) of patients had undergone endoscopy procedures. CONCLUSION: Inappropriate use of PPI remains common in hospital practice. The risks of using long-term PPI must be weighed against the benefits.

A comparative study of renal dysfunction in patients with inflammatory arthropathies: strong association with cardiovascular diseases and not with anti-rheumatic therapies, inflammatory markers or duration of arthritis.

AIMS: The aim of this study was to investigate the prevalence of chronic kidney disease (CKD) among comparable patients with rheumatoid arthritis (RA) and seronegative inflammatory arthritis, and to explore any predictive factors for renal impairment. METHODS: Consecutive patients with peripheral joint disease (oligo and polyarthritis) were recruited from our inflammatory arthritis clinics. We divided patients in two groups: RA group and seronegative inflammatory arthritis group. The cohort consisted of 183 patients (RA = 107, seronegative arthritis = 76 [psoriatic arthritis = 69, undifferentiated oligoarthritis = 7]). Estimated glomerular filtration rate (eGFR) was calculated using the established Modification of Diet in Renal Disease equation. Demographic details, disease-specific characteristics, anti-rheumatic drugs and the presence of cardiovascular diseases were recorded. RESULTS: In total, 17.48% (n = 32) of the cohort had CKD. There was no statistically significant variation between the two groups as regards baseline demographics, disease characteristics, use of anti-rheumatic drugs and the presence of individual cardiovascular diseases. We found that eGFR and the presence of CKD were similar among these groups. Among patients with CKD, 72% had undiagnosed CKD. No association of statistical significance was noted between CKD and the use of corticosteroids, disease-modifying antirheumatic drugs and anti-tumor necrosis factor agents. The association of cardiovascular diseases with CKD remained significant after adjusting for confounders (age, gender, duration of arthritis, high C-reactive protein, use of anti-rheumatic drugs). CONCLUSIONS: Patients with inflammatory arthritis are more prone to have CKD. This could have serious implications, as the majority of rheumatology patients use non-steroidal anti-inflammatory drugs and different immunosuppressives, such as methotrexate. No association of kidney dysfunction was noted with inflammatory disease-specific characteristics; rather it appears to have a positive independent association with cardiovascular diseases.

Perceptions and attitudes of hospital staff toward paging system and the use of mobile phones.

OBJECTIVES: Our objective was to document the pattern of mobile phone usage by medical staff in a hospital setting, and to explore any perceived benefits (such as improved communications) associated with mobile phones. METHODS: This cross-sectional survey was conducted in Waterford Regional Hospital, Ireland, where bleep is the official system of communication. All non-consultant hospital doctors, of medical disciplines only, were asked to participate. The questionnaire was designed to explore the pattern and different aspects of mobile phone usage. RESULTS: At the time of study, there were sixty medical junior doctors, and the response rate was 100 percent. All participants used mobile phones while at work, and also for hospital-related work. For 98.3 percent the mobile phone was their main mode of communication while in the hospital. Sixty-two percent (n = 37) made 6-10 calls daily purely for work-related business, and this comprised of ≥ 80 percent of their daily usage of mobile phones. For 98 percent of participants, most phone calls were work-related. Regarding reasons for using mobile phones, all reported that using mobile phone is quicker for communication. CONCLUSIONS: Mobile phone usage is very common among the medical personnel, and this is regarded as a more efficient means of communication for mobile staff than the hospital paging system.

A case of cetuximab-related tumour lysis syndrome in metastatic rectal carcinoma.

A 60-year-old man was diagnosed with a moderately differentiated adenocarcinoma in November 2006. The computed tomography (CT), magnetic resonance imaging (MRI) and whole-body positron emission tomography-CT (PET-CT) scan showed the presence of multiple liver metastases which were confined to its right lobe. He had the first session of a combined therapy with cetuximab and 5-fluorouracil (5-FU) in March 2009; however, soon afterwards, he presented with the symptoms, signs and biochemistry suggestive of tumour lysis syndrome. Our unusual case highlights that tumour lysis syndrome can also develop in 'low risk' category tumours, and that clinicians should be vigilant in identifying at-risk patients.

Short- and long-term response of sunflower to airborne bromoxynil-octanoate under controlled and field conditions.

Wind tunnel studies and a field study were conducted to investigate the impact of the airborne herbicide bromoxynil-octanoate on non-target plants. Sunflowers at the two-leaf stage were used as test plants and exposed for 24 h in a wind tunnel to a range of concentrations of airborne bromoxynil-octanoate. Quantum yield of electron transport at Photosystem II (phiPSII) of exposed leaves and leaves developed after exposure, plant height, days to flower and head diameter were used to determine the short- and long-term response of sunflowers to bromoxynil-octanoate. Quantum yield of exposed leaves and of the second leaf pair, determined 1 h and 2 days after exposure, was reduced at concentrations >0.449 and >1.159 microg/m3, respectively, but no effects on further leaf pairs developed after exposure were observed. Growth parameters were partly affected when exposed to >1.448 microg/m3. In a field study a maize plot was treated with bromoxynil-octanoate and parathion-methyl, used as a tracer compound. Afterwards, potted sunflowers were placed inside the maize plot and at different distances (2, 4, 8 and 16 m) from the treated plot. The highest concentrations of bromoxynil-octanoate and parathion-methyl collected in air samples at a distance of 8 m outside of the treated plot were 0.100 and 0.055 microg/m3, respectively. Little of the breakdown product bromoxynil phenol was detected in the air. Detectable concentrations of bromoxynil-octanoate and bromoxynil phenol were found only in a few leaf samples, whereas parathion-methyl was detected in almost 50% of the leaf samples up to 16 m from the treated plot. Quantum yield and growth of sunflower were not affected due to low concentrations of bromoxynil-octanoate in the air.

Solvolysis procedures for the determination of bound residues of the mycotoxin deoxynivalenol in fusarium species infected grain of two winter wheat cultivars preinfected with barley yellow dwarf virus.

A trichloroacetic acid treatment at 140 degrees C for 40 min was successfully established as a suitable solvolysis procedure for the recovery of bound deoxynivalenol or its derivatives in Fusarium-infected plants. Deoxynivalenol itself was not decomposed in the procedure. The derivative 15-acetyl-deoxynivalenol was chosen as a model compound for setting free deoxynivalenol in an acid-catalyzed deesterification reaction, developing the method. This is the first report using a trichloroacetic acid solvolysis procedure as a sample incubation step to free bound deoxynivalenol and determine free from bound deoxynivalenol in the sample. Between 13 and 63% of the total deoxynivalenol consisted of nonextractable deoxynivalenol. Deoxynivalenol contents in grain of the susceptible cultivar "Agent" infected with Fusarium spp. were 12-24 times higher when compared to those for the corresponding moderately resistant cultivar "Petrus". The highest deoxynivalenol amounts were determined in grain infected with Fusarium spp. as well as simultaneously infected with BYDV. This solvolysis procedure may be of importance for distinguishing between resistant and susceptible plants and their ability to immobilize (bound) mycotoxins as a plant defense mechanism.