Evidence of Antineutrinos from Distant Reactors Using Pure Water at SNO.

The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.

Evaluation of an adult immunization composite measure in the Indian Health Service.

BACKGROUND: Government agencies, healthcare accreditation bodies and quality improvement organizations support the development of new quality measures. Composite quality measures use more than one measure to develop a broader assessment of healthcare system function. Currently, no composite measures for adult immunization coverage exist. Development of such measures could facilitate improvements in adult immunization coverage by focusing on measurement of receipt of all age-recommended vaccines. METHODS: We recruited five Indian Health Service (IHS) and Tribal health clinics to pilot an Adult Immunization Composite Measure (AICM). Data were collected monthly over seven months using a pre-programmed electronic health record (EHR) reporting tool (IHS sites); Tribal sites used third-party software or a programmable EHR reporting function. Data collected included: number of adults aged 19 years and over who were active users of the facility with at least two visits in the last three years; the cumulative number fully immunized per age-based recommendations for tetanus toxoid-containing vaccines, pertussis, zoster and pneumococcal vaccines; and the percent immunized for the AICM and for each individual vaccine. Coverage was calculated for three age groups: 19-59 years; 60-64 years; and 65 years and older. RESULTS: All sites reported aggregate immunization data monthly from patient EHR records. For all adults 19 years and older, AICM coverage ranged from 49% to 87% at the end of the report period. Two sites showed increases in AICM coverage ≥ 3%. Improvements in zoster vaccine coverage accounted for most of the increase observed. One site specifically focused on improving zoster coverage as a result of using the AICM. CONCLUSIONS: We demonstrated the feasibility of implementing a composite measure of adult immunization coverage. This is the first measure capable of monitoring immunization completeness, coverage improvement and overall adult vaccine program effectiveness for adults who receive all recommended, age-based vaccines.

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10-4) compared with either PBF- (P=1.5 × 10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10-5) and disease-free survival (P=4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth.

We previously identified CLEC14A as a tumour endothelial marker. Here we show that CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a human umbilical vein endothelial cell spheroid-sprouting assay, we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a(+/+) and clec14a(-/-) mice revealed defects in sprouting angiogenesis in CLEC14A-deficient animals. Tumour growth was retarded and vascularity reduced in clec14a(-/-) mice. Pull-down and co-immunoprecipitation experiments confirmed that MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4, but not C2, blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4-treated animals and vascular density was also reduced in the C4-treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, which has the potential to be manipulated in future antiangiogenic therapy design.

Client satisfaction and weight loss outcomes of student centred dietetic outpatient clinics.

AIM: Evaluation of health care services and providers is essential in determining effectiveness and quality. The aim of this study was to assess the client satisfaction and weight loss outcomes of student focussed dietetic outpatient weight loss clinics. METHODS: The outpatient clinics were conducted by the University as part of student education. Sixty-one clients attended a new appointment during 2008. Anthropometric and demographic details were extracted from clients' clinic records. Clients were mailed a 30-item satisfaction survey adapted from an existing instrument. RESULTS: Twenty-six surveys were returned (43% response rate). Respondents were less likely to be satisfied with appointment wait times and availability of parking (65%, 70%, respectively) compared with other factors. Dietitians were seen as polite and courteous, and the presence of students did not lessen the attention from the dietitian. Mean (SD) weight change was -3.3 (3.2) kg over 12 months (P < 0.05, n = 20). CONCLUSION: It was found that clients were satisfied with services and while statistically significant weight loss was achieved, results did not reach the clinically significant weight loss of 5% of initial weight.

[Therapeutic effect of encapsulated into the nanocontainers MBP immunodominant peptides on EAE development in DA rats].

Multiple Sclerosis (MS) is a serve autoimmune neurodegenerative disease. Development of innovative approaches of MS treatment is of a high priority in the modern immunology and pharmacy. In the present study we showed high therapeutic efficiency of immunodominant peptides of myelin basic protein (MBP) incorporated into the monolayer mannosylated liposomes on the development of experimental autoimmune encephalomyelitis (EAE) in DA rats. MBP is a component ofoligodendrocytes' membrane, which form axonal sheath, and is one of the major autoantigens in MS. We analyzed binding pattern ofanti-MBP autoantibodies from MS patients using previously designed MBP epitope library. Utilizing the same approach we investigated pool of anti-MBP antibodies from SJL/J and C57/BL6 mice and DA rats with induced EAE. The most relevant rodent model to MS was EAE in DA rats according to the autoantibodies' binding pattern. We selected three immunodominant MBP fragments encapsulated in monolayer mannosylated liposomes for the following treatment of verified DA rodent model. MBP fragment 46-62 was the most effective in reducing of the first EAE attack, whereas MBP 124-139 and 147-160 inhibited development of pathology during remission stage. Simultaneous administration of these peptides in liposomes significantly decreased level of anti-MBP antibodies. Synergetic therapeutic effect of MBP fragments reduced integral disease score by inhibiting first EAE wave and subsequent remission, thus, our findings disclosure novel approaches for efficient treatment of Multiple Sclerosis.

Galanin acts as a trophic factor to the central and peripheral nervous systems.

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly up-regulated in many neuronal tissues after nerve injury or disease. Over the last 10 years, we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. Most recently, we have shown that galanin expression is markedly up-regulated in multiple sclerosis (MS) lesions and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Over-expression of galanin in transgenic mice abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or GalR2 increase disease severity. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.

Galanin acts as a trophic factor to the central and peripheral nervous systems.

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly upregulated in many neuronal tissues after nerve injury or disease. Over the last 10 years we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.

Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer.

Hypoxia, via the hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2), upregulates many genes involved in cell survival. However, proapoptotic pathways are also induced. BCL-2/adenovirus E1B-19 kDa-interacting protein 3 (BNIP3) represents a paradigm of a cell death protein that is hypoxically upregulated via HIF-1 in most cancers. We found that in contrast to many other cell types, 6/8 colorectal cancer (CRC) cell lines show little hypoxic induction of BNIP3 despite an intact HIF signalling system. Colorectal tumour tissue also loses BNIP3 expression relative to matched normal samples. Downregulation of hypoxic BNIP3 in CRC cells was independent of the expression of other BCL-2 family members, or BNIP3L. That BNIP3 plays a functional role in hypoxic survival in CRC cells was demonstrated by the fact that CRC cell lines that do not upregulate BNIP3 or have been treated with BNIP3 RNA interference were insensitive to hypoxia-induced cell death. Promoter methylation and histone deacetylation were shown to silence BNIP3 in these CRC cell lines. Of significance, hypoxic induction of BNIP3 was restored in 4/6 cell lines by trichostatin-A treatment alone. These data suggest that BNIP3 plays an important role in hypoxic cell death and epigenetic mechanisms selectively silence its expression in CRC.

Crisis management during anaesthesia: awareness and anaesthesia.

BACKGROUND: Patient awareness during general anaesthesia has considerable potential for severe emotional distress in the patient as well as professional, personal, and financial consequences for the anaesthetist. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for awareness, in the detection and management of potential awareness in association with general anaesthesia. METHOD: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: Of the first 4000 reports received by AIMS, there were 21 incidents of patient awareness under general anaesthesia, and 20 of patients being paralysed while awake from "syringe swaps" before induction of anaesthesia. In 12 of the 21 reports there was an obvious cause, most commonly a low concentration of volatile agent (8 of 12 reports). The AIMS "core" crisis management algorithm would have detected the cause of awareness in all of these cases. In nine reports the course of anaesthesia appeared unremarkable, and in these the algorithm would not have been expected to detect or prevent awareness. Volatile agent monitoring would have prevented some cases of awareness, as would bispectral index electroencephalographic (BIS) monitoring. The role of BIS monitoring is still contentious, but it should be considered for high risk patients. CONCLUSION: Awareness should be minimised by thorough checking of equipment, particularly vaporisers, and frequent application of a structured scanning routine. Awareness may occur during crisis management and aftermath protocols should include patient follow up to detect and manage awareness when it occurs.

Crisis management during anaesthesia: pneumothorax.

BACKGROUND: Pneumothorax is a potentially dangerous condition which may arise unexpectedly during anaesthesia. The diagnosis is one of exclusion, as initial changes in vital signs (cardiorespiratory decompensation and difficulty with ventilation) are non-specific, and other causes of such changes are more common, whereas local signs may be difficult to elicit, especially without full access to the chest. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for pneumothorax, in the management of pneumothorax occurring in association with anaesthesia. METHODS: Reports of pneumothorax were extracted and studied from the first 4000 incidents reported to the Australian Incident Monitoring Study (AIMS). The potential performance of the structured approach, using the combination of algorithims described above for each of the relevant incidents, was compared with the actual management as reported by the anaesthetists involved. RESULTS: Pneumothorax was noted as a possible diagnosis in 65 reports; 24 cases had a confirmed pneumothorax, of which 17 were in association with general anaesthesia. It was considered that, correctly applied, the application of the algorithms would have led to earlier recognition of the problem and/or better management in 12% of cases. CONCLUSION: Any pneumothorax may become a dangerous tension pneumothorax with the application of positive pressure ventilation. Limited access to the chest during anaesthesia may compromise the diagnosis. Recognition of any preoperative predisposition to a pneumothorax (for example, iatrogenic or traumatic penetrating procedures around the base of the neck) and close communication with the surgeon are important. Aspiration diagnosis in suspected cases and correct insertion of a chest drain are essential for the safe conduct of anaesthesia and surgery.

Crisis management during anaesthesia: anaphylaxis and allergy.

BACKGROUND: Anaphylactic and anaphylactoid reactions during anaesthesia are a major cause for concern for anaesthetists. However, as individual practitioners encounter such events so rarely, the rapidity with which the diagnosis is made and appropriate management instituted varies considerably. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for anaphylaxis, in the management of severe allergic reactions occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual performance as reported by the anaesthetists involved. RESULTS: There were 148 allergic reactions among the first 4000 incidents reported to AIMS. It was considered that, properly applied, the structured approach would have led to a quicker and/or better resolution of the problem in 30% of cases, and would not have caused harm had it been applied in all of them. CONCLUSION: An increased awareness of the diverse clinical manifestations of allergy seen in anaesthetic practice, together with the adoption of a structured approach to management should improve and standardise the treatment and improve follow up of patients suspected of having suffered a significant allergic reaction under anaesthesia.

Crisis management during anaesthesia: recovering from a crisis.

Preventing harm to the patient is the priority during a crisis. After a major incident, and especially when a patient has been harmed, there are a number of matters to be addressed: the ongoing care of the patient; documentation of the incident; investigation of the root causes; completion of reports; interviews with the patient and/or the next of kin, together with apologies and expression of regret; updates and ongoing support for friends and relatives; a word of thanks to the staff involved for their assistance; formal debriefing of staff for quality assurance and possibly ongoing support and a separate debriefing for psychological purposes; ensuring that the recommendations of the root cause analysis are carried out; or, failing that, that the issues are logged on a risk register. The extent and depth of the follow up protocol depends on what, if any, harm may have been done. This may constitute completion of an incident report; notification of an equipment failure to a federal regulatory authority; arranging consultations with a mental health professional to manage psychological sequelae (especially following an awareness episode); follow up during weeks of intensive care treatment; or, when a death has occurred, a full medico-legal and/or coronial set of procedures. A precis is appended in an action card format.

Targeted disruption of galanin: new insights from knock-out studies.

The neuropeptide galanin has a widespread but no means ubiquitous expression pattern in the nervous and endocrine systems. Profound changes in the levels and distribution of the peptide occur in a range of path-physiological situations including nerve injury or damage and alterations in the circulating levels of a number of hormones. There is now a substantial body of work to indicate that galanin plays an important biological role as a regulator of neurotransmitter and hormone release in the adult. The recent generation of mice carrying a loss-of-function mutation within the galanin gene has allowed us new insights into the physiological actions of galanin. In this manuscript we detail three sets of data relating to the major phenotypic effects thus far delineated, putting them in the context of existing published data. These studies demonstrate that galanin acts as a developmental and trophic factor to subsets of neurons in the nervous and neuroendocrine systems.

Spontaneous foreign body extrusion following perforating eye injury.

A structured approach to the management of a perforating ballistic eye injury is illustrated in this case, where initial treatment was limited to simple corneal wound closure and antibiotic prophylaxis. A pellet had passed completely through the globe but the retina remained attached, and it was decided to manage the case conservatively. Two retained foreign bodies were extruded spontaneously some months after the injury when suture removal and delayed cataract surgery led to a virtually perfect visual outcome. The patient has had no further complications at least three years after initial injury. The management of this civilian case illustrates some basic concepts in treating ballistic eye injuries that may be applicable in a military setting.

The importance of the short-term leaching dynamics of wood preservatives.

The potential environmental impacts from the use of treated timber in aquatic areas is under scrutiny as a result of environmental legislation and reports of the deleterious environmental effects around treated structures. In this study leaching experiments of up to 3 weeks duration were conducted on two species of chromated copper arsenate treated timber, dried for different periods of time. Increased drying time significantly reduced leaching of Cr and As. The addition of a synthetic humic acid increased leaching of Cu and As, but reduced leaching of Cr. Putative risk assessments conducted using short-term copper leaching data suggested protocol design may influence decisions made regarding the environmental acceptability of such preservatives.