Unfolded p53 in non-neuronal cells supports bacterial etiology of Alzheimer's disease.

Alzheimer's disease has proven to be largely intractable to treatment, despite years of research, and numerous trials of therapies that target the hallmarks of the disease - amyloid plaques and neurofibrillary tangles. The etiology of Alzheimer's disease remains elusive. There is a growing body of evidence for an infectious trigger of Alzheimer's disease, and, in particular, the focus has been on the oral pathogen Porphyromonas gingivalis (P. gingivalis). Reports of the expression of a misfolded form of p53 in non-neuronal cells (fibroblasts, peripheral blood mononuclear cells, and B cells) and serum, which appears several years before clinical symptoms manifest, may provide further support for the role of bacteria in general, and P. gingivalis in particular, in the initiation of the disease. This review presents a model of the pathway from initial oral infection with P. gingivalis to amyloid plaque formation and neuronal degeneration, via the steps of chronic periodontitis; secretion of the inflammagens lipopolysaccharide and gingipains into the bloodstream; induction of an inflammatory response in both peripheral cells and tissues; disruption of the blood-brain barrier, and entry into the central nervous system of the inflammagens and the P. gingivalis bacteria themselves. In this model, the misfolded p53 (or "unfolded p53"; up53) is induced in non-neuronal cells and upregulated in serum as a result of oxidative stress due to lipopolysaccharide from P. gingivalis. up53 is therefore a potential biomarker for early diagnosis of the presence of a causative agent of Alzheimer's disease. Fastidious dental hygiene and aggressive antibiotic treatment may prevent the patient progressing to clinical Alzheimer's disease if serum up53 is detected at this pre-symptomatic stage.

Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis.

Fungi are important infectious disease-causing agents, but are often overlooked as environmental factors in disease. We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease. Approximately 90% cases of ALS are sporadic, and the aetiology of sporadic ALS is still unknown. We have previously postulated that grass or soil-associated fungal infections may be a leading cause of sporadic ALS. Herein we extend this proposal to water-associated fungi. A wide variety of fungi have been reported in drinking water including Acremonium, Alternaria, Aspergillus, Cladosporium, Fusarium, Penicillium and Trichoderma. Some of these are known to produce neurotoxic mycotoxins. Despite this, drinking water is not routinely monitored for fungal contamination. Fungal contamination could explain the close correlation between distribution of well water and cases of sporadic ALS in the United States. We propose several mechanisms by which an opportunistic fungal infection from environmental exposure (to water, soil or plants) can lead to long term neuronal degradation resulting in the hallmarks of ALS. If confirmed, the association between fungal infection and sporadic ALS could lead to novel treatment strategies for this progressive and fatal disease.

Fungal Neurotoxins and Sporadic Amyotrophic Lateral Sclerosis.

We review several lines of evidence that point to a potential fungal origin of sporadic amyotrophic lateral sclerosis (ALS). ALS is the most common form of motor neuron disease (MND) in adults. It is a progressive and fatal disease. Approximately 90% cases of ALS are sporadic, and 5-10% are due to genetic mutations (familial). About 25 genes implicated in familial ALS have been identified so far, including SOD1 and TARDBP, the gene encoding 43 kDa transactive response (TAR) DNA-binding protein (TDP-43). Despite intensive research over many decades, the aetiology of sporadic ALS is still unknown. An environmental cause, including grass or soil-associated fungal infections, is suggested from a range of widely diverse lines of evidence. Clusters of ALS have been reported in soccer players, natives of Guam and farmers. Grass-associated fungi are known to produce a range of neurotoxins and, in symbiotic associations, high levels of fungal SOD1. Exposure of neurons to fungal neurotoxins elicits a significant increase in glutamate production. High levels of glutamate stimulate TDP-43 translocation and modification, providing a link between fungal infection and one of the molecular and histologic hallmarks of sporadic ALS. A recent study provided evidence of a variety of fungi in the cerebrospinal fluid and brain tissue of ALS patients. This review provides a rational explanation for this observation. If a fungal infection could be confirmed as a potential cause of ALS, this could provide a straightforward treatment strategy for this fatal and incurable disease.

Circulating Phospholipids as Biomarkers of Breast Cancer: A Review.

Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. The key to surviving breast cancer is early detection and treatment. Current technologies rely heavily on imaging of the breast, and although considered the gold standard, they have their limitations. There is a need for a more accurate screening test for women of all ages, which can detect the cancer at a cellular level and before metastasis. There have been extensive studies into markers for breast cancer including protein and nucleic acid biomarkers, but to date, these have been unsuccessful. A growing field of interest is the association between breast cancer (tissue and cells) and lipids, which is documented in the literature, and may be considered as a leading candidate in the breast cancer detection space.

Size unbiased representative enzymatically generated RNAi (SURER) library and application for RNAi therapeutic screens.

RNA interference (RNAi) libraries screens have become widely used for small RNA (sRNA) therapeutic targets development. However, conventional enzymatically libraries, typically prepared using the type 2 restriction enzyme MmeI, produce sRNAs between 18 and 20 bp, much shorter than the usual lengths of 19-23 bp. Here we develop a size unbiased representative enzymatically generated RNAi (SURER) library, which employs type 3 restriction modification enzyme EcoP15I to produce sRNAs ranging from 19 to 23 bp using a group of rationally designed linkers, which can completely mimic the length of sRNAs naturally generated by Dicer enzyme in living cells, and the screening results of SURER libraries showed high recombination rate and knockdown efficiency. SURER library provides a useful tool for RNAi therapeutics screening in a fast and simple way.

Identification of breast cancer-associated lipids in scalp hair.

A correlation between the presence of breast cancer and a change in the synchrotron-generated X-ray diffraction (XRD) pattern of hair has been reported in several publications by different groups, and on average XRD-based assays detect around 75% of breast cancer patients in blinded studies. To date, the molecular mechanisms leading to this alteration are largely unknown. We have determined that the alteration is likely to be due to the presence of one or more breast cancer-associated phospholipids. Further characterization of these lipids could be used to develop a novel, sensitive and specific screening test for breast cancer, based on hair initially, and potentially extendable to other biological samples.

Gene silencing of IL-12 in dendritic cells inhibits autoimmune arthritis.

BACKGROUND: We have previously demonstrated that immune modulation can be accomplished by administration of gene silenced dendritic cells (DC) using siRNA. In this study, we demonstrate the therapeutic utilization of shRNA-modified DC as an antigen-specific tolerogenic vaccine strategy for autoimmune arthritis. METHODS: A shRNA that specifically targets IL-12 p35 was designed and cloned into a plasmid vectors (IL-12 shRNA). Bone marrow-derived DC from DBA/1 mice were transfected with the IL-12 shRNA construct in vitro. Mice with collagen II (CII)-induced arthritis (CIA) were treated with the modified DCs expressing the shRNA. Recall response and disease progression were assessed. RESULTS: After gene silencing of IL-12 in DC, DC were shown to selectively inhibit T cell proliferation on recall responses and in an MLR. In murine CIA, we demonstrated that administration of IL-12 shRNA-expressing DC that were pulsed with CII inhibited progression of arthritis. The therapeutic effects were evidenced by decreased clinical scores, inhibition of inflammatory cell infiltration in the joint, and suppression of T cell and B cell responses to CII. CONCLUSION: We demonstrate a novel tolerance-inducing protocol for the treatment of autoimmune inflammatory joint disease in which the target antigen is known, utilizing DNA-directed RNA interference.

Detecting the presence of denatured human serum albumin in an adsorbed protein monolayer using TOF-SIMS.

We demonstrate the application of time-of-flight secondary ion mass spectrometry (TOF-SIMS) in conjunction with multivariate statistics to differentiate trace levels of denatured proteins in adsorbed monolayers; specifically, human serum albumin (HSA) on oxidized silicon substrates. Subtle differences in protein conformation due to thermal denaturation of HSA, unable to be determined by dynamic light scattering nor circular dichroism, were differentiated by TOF-SIMS. The fragmentation pattern is highly sensitive to protein conformation, allowing assessment of relative amounts of proteins in mixtures and quantifying amounts of denatured protein in a sample. Discussion is presented on ascribing orientation and conformational differences between samples based upon TOF-SIMS spectra. This has implications for detecting denatured protein in biotechnology and medical applications.

Characterization of a Test for Invasive Breast Cancer Using X-ray Diffraction of Hair-Results of a Clinical Trial.

OBJECTIVE: To assess the performance of a test for breast cancer utilizing synchrotron x-ray diffraction analysis of scalp hair from women undergoing diagnostic radiology assessment. DESIGN AND SETTING: A double-blinded clinical trial of women who attended diagnostic radiology clinics in Australia. PATIENTS: 1796 women referred for diagnostic radiology, with no previous history of cancer. MAIN OUTCOME MEASURES: Sensitivity, specificity and accuracy of the hair test analysis compared to the gold standard of imaging followed by biopsy where indicated. RESULTS: The hair-based assay had an overall accuracy of >77% and a negative predictive value of 99%. For all women, the sensitivity of both mammography and X-ray diffraction alone was 64%, but when used together the sensitivity rose to 86%. The sensitivity of the hair test for women under the age of 70 was 74%. CONCLUSION: In this large population trial the association between the presence of breast cancer and an altered hair fibre X-ray diffraction pattern previously reported has been confirmed. It appears that mammography and X-ray diffraction of hair detect different populations of breast cancers, and are synergistic when used together.

Diagnosis of breast cancer by X-ray diffraction of hair.

This article presents the results of analyses of hair fibers from women with breast cancer using synchrotron-derived X-ray diffraction. These diffraction patterns contained a new feature superimposed on the normal diffraction pattern of alpha-keratin. The feature appeared as a ring with a molecular spacing determined to be 4.76 +/- 0.07 nm. This feature was not present in the diffraction patterns of hair from women without breast cancer as assessed by other routine clinical diagnostic techniques. Furthermore, different hairs from the same subject analysed on two different synchrotron beamlines give remarkably consistent diffraction patterns. Previous studies by other investigators have suggested that analysis of X-ray diffraction patterns of hair can reveal the presence of breast cancer in clinical and preclinical trials. This finding, however, has not been independently confirmed. The methodologies of sample handling, sample exposure and image analysis are known to be vital. We discuss some of these issues and provide a detailed description of the methodology employed for the sample handling and image analysis and new methodologies developed from this work. We conclude that X-ray diffraction of hair has the potential to provide a non-invasive test for the presence of breast cancer.

Computerized mental health assessment in integrative health clinics: a cross-sectional study using structured interview.

Computerized mental health assessment is gaining popularity. It enables the standardization of assessment of clinical problems, increases the capacity to collect sensitive or confidential information, facilitates personal assessment at one's own pace, and offers rapid screening of mental health status. The use of computer technology to conduct mental health assessment was an initiative proposed for two nurse-led integrative health clinics affiliated to a University in Hong Kong. It was intended to provide an efficient screening for depression, anxiety, alcohol abuse, and problem gambling common in the primary health-care settings to facilitate early intervention. This study was conducted to assess the effectiveness of using a computerized health assessment kiosk to perform mental health assessment. The assessment items were derived from an abbreviated World Health Organization Mental Disorders Checklist and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Criteria for Pathological Gambling. The study involved an opportunity sample of 31 subjects who volunteered to complete the computerized mental health assessment during their waiting time in the clinics. The results showed that most subjects had positive feelings about using a computer to perform a mental health assessment and had increased understanding of their mental health. Suggestions made to improve computerized mental health assessments included touch screen, voice instructions, and enlarged print font size.

The validity and reliability of the World Health Organization Mental Disorders Checklist for use in a telehealth clinic in Hong Kong.

This research aimed to test the validity and reliability of the 'World Health Organization Mental Disorders Checklist' for use in a telehealth clinic in Hong Kong. The Checklist adopted four subscales: (i) depression; (ii) anxiety; (iii) alcohol use disorders; and (vi) functioning and disablement, and was translated from English into Chinese. It was validated by a panel of five experts to confirm its content validity (content validity index = 0.98) and cultural appropriateness in Hong Kong. The reliability of the checklist was supported by the findings of a test-retest procedure (Pearson correlation = 0.66-0.88, P < 0.01), internal consistency reliability (Cronbach's alpha = 0.54-0.83), and interrater reliability (Kendall's coefficient of concordance = 0.58-1.00, P < 0.01) involving a sample of 197 subjects from one telehealth clinic in Hong Kong.

Application of biosolids in mineral sands mine rehabilitation: use of stockpiled topsoil decreases trace element uptake by plants.

Mineral sands mining involves stripping topsoil to access heavy-mineral bearing deposits, which are then rehabilitated to their original state, commonly pasture in south-west Western Australia. Organic amendments such as biosolids (digested sewage sludge) can contribute organic carbon to the rehabilitating system and improve soil chemical fertility and physical conditions. Use of biosolids also introduces the risk of contamination of the soil-plant system with heavy metals, but may be a useful source of trace elements to plants if the concentrations of these elements are low in unamended soil. We expected that biosolids amendment of areas mined for mineral sands would result in increased concentrations of metals in soils and plants, and that metal uptake would be decreased by adding stockpiled topsoil or by liming. A glasshouse experiment growing a mixed annual ryegrass (Lolium rigidum)-subterranean clover (Trifolium subterraneum) sward was conducted using two soil materials (residue sand/clay and conserved topsoil) from a mineral sands mine amended with different rates of biosolids (0, 10, 20, 50 dry t/ha), and including a liming treatment (2 t/ha). Total concentrations of metals (As, Cd, Co, Cr, Cu, Ni, Pb and Zn) in soil increased with increasing rate of biosolids application. Metal uptake was generally lower where topsoil was present and was decreased by liming. With increasing biosolids application, plant metal concentrations increased for Cd, Ni and Zn but decreased or were erratic for other elements. In clover, biosolids application removed the Zn deficiency observed where biosolids were not applied. Plant uptake of all elements increased with increasing biosolids application, suggesting dilution by increased plant biomass was responsible for erratic metal concentration results. Despite the observed increases in uptake of metals by plants, metal concentrations in both species were low and below food standard thresholds. It is unlikely that a single application of biosolids in this system posed a threat from heavy metal contamination of soils or plants, and was beneficial in terms of Zn nutrition of T. subterraneum.

Minimizing fire risk during eye surgery.

Supplemental oxygen under the drapes in high concentrations can lead to fires in ophthalmic theaters. This study attempted to eliminate the fire risk while maintaining the required therapeutic effect. The sample consisted of 201 patients undergoing ophthalmic surgery, with 104 subjects in the control group and 97 in the experimental group. A quasi-experimental design compared the existing method of oxygen administration (100% supply) with a new method (experimental) providing 24% oxygen supply. Measurements of the oxygen concentration were taken along with the fractional inspiratory carbon dioxide (FiCO2), the peripheral oxygen saturation (SpO2), the end tidal carbon dioxide (ETCO2), and the respiratory rate (RR). There was a significant difference in oxygen and carbon dioxide concentrations under the drapes (p <.05). The fractional inspiratory carbon dioxide was reduced in the experimental group. The new method was adopted to reduce the risk of fire in ophthalmic operating theaters.

A Delphi survey of evidence-based nursing priorities in Hong Kong.

The purpose of this study was to inform an evidence-based nursing development project within the Hospital Authority, Hong Kong. It considered the specific question of: what are the nursing practice issues which need to be addressed as a matter of priority in order to improve nursing practice, the quality of care or develop some aspect of nursing practice. A three round Delphi survey was adopted. The methodological problems associated with the use of the Delphi method are addressed. An expert panel consisting of 190 Department Operations Managers (nurses) was identified. The data collection focused on issues related to nursing skills and client care and excluded management or educational issues. Agreed categories were prioritized in the final round by utilizing a 11-point rating scale. The group mean score for each category was calculated and rank ordered. The results provided 45 categories that reflected the nursing practice priorities that required more research evidence to guide practice. The top five ranked items were: nurse patient communication, resuscitation, administration of medicines, counselling and nursing documentation. The top 10 items were used to inform the advisory and selection processes for the evidence-based practice development project.

A controlled trial of music and pre-operative anxiety in Chinese men undergoing transurethral resection of the prostate.

AIM OF THE STUDY: To test the effects of music intervention on pre-operative anxiety in Chinese males undergoing transurethral resection of the prostate. RATIONALE: No studies have measured the effects of music intervention in reducing pre-operative anxiety for patients with transurethral resection of the prostate (TURP). Previous studies have examined the effects of music on pre-operative anxiety but have not examined the possible effects of the presence of a carer as an independent variable in pre-operative anxiety levels of patients in addition to the music intervention. The cultural validity of applying a music intervention to the reduction of pre-operative anxiety was also investigated. DESIGN: A quasi-experimental design with three groups: music intervention, nurse presence and control group. METHOD: Thirty patients having TURP were randomly assigned (n = 10 each group) to one of the three groups. Pre- and post-test measures of systolic and diastolic blood pressure, heart rate and state anxiety using the Chinese State-Trait Anxiety Inventory (C-STAI) were obtained for the three groups. RESULTS: The findings showed that the music intervention significantly reduced all blood pressure levels for the patients. A reduction in state anxiety level was also found for the music intervention group. No significant reductions in blood pressure, heart rate and state anxiety level were found in the nurse presence and control groups. CONCLUSION: The results support the cross-cultural validity of using a music intervention in pre-operative anxiety reduction, in this case for TURP patients waiting in the theatre holding area.

The efficiency of fluid balance charting: an evidence-based management project.

This study began following an observation that fluid balance (FB) charts seemed to be overloading medical records in Hong Kong hospitals. The major issues for this study were the efficiency and appropriateness of FB charting. The study design included an analysis of 250 medical records and an opinion survey. Seventy-five doctors and 98 nurses participated in the survey. The results indicated that 50% of all medical records had FB charts and in these cases they made up between 12 and 16% of the whole medical record. Intravenous infusion and urinary catheterization accounted for almost 70% of the recorded reasons for using them. Thirty-two per cent of FB charts were found to be incomplete or inaccurate. Forty-six per cent of doctors and nurses reported that they believed that charts were not always terminated when they were not required. The most common belief among doctors was that only doctors should discontinue the FB charts. Nurses were almost unanimous in believing that they should not do this without the agreement of the doctors! It was concluded that nurses in the context under study should be empowered to terminate charts when they become unnecessary. In addition, the design of charts should be modified to accommodate different purposes.

What is the evidence on evidence-based nursing? An epistemological concern.

AIM: This paper adopts an epistemological perspective in order to support the assertion that there is very little evidence to support the existence of evidence-based nursing as a distinct construct or process. RATIONALE: This analysis of concept meaning is based on the theory of symbolic interactionism. By adopting this theory the commonalities and inconsistencies in the use of evidence-based symbolism by nurses and other health care professionals can be used to evaluate the perceived meaning of the term. METHODS: A frequency analysis of relevant key words in one publications data-base demonstrates the increasing use of evidence-based terminology and its euphemistic status visa vi research. An epistemological analysis is conducted on a sample of concept clarification statements taken from the popular literature, defining the nature of 'evidence' and 'evidence-based practice'. FINDINGS: The results of the frequency analysis show that the keywords 'evidence-based medicine' revealed 5612 papers, evidence-based practice (EBP) 432 papers, evidence-based nursing 47 papers, evidence-based health care 60 papers, and evidence-based decision making 43. Almost all of these papers have been published since 1995 and the earliest use of the symbol 'evidence-based' is 1992. There is also an increase in papers adopting 'evidence-based' symbolism along with a commensurate decrease in the use of the term 'research' in the nursing context. CONCLUSION: 'Evidence-based practice' is commonly a euphemism for information management, clinical judgement, professional practice development or managed care. There is insufficient evidence to demonstrate that evidence-based nursing is a single construct or process that can be distinguished from its concomitants. The term adds little more to the existing long standing traditions of quality assurance and research-based practice. Nurses must avoid the inefficiency brought about by the 'intense enthusiasm followed by sad disenchantment' that has been associated with other attempts to introduce innovation in health care delivery (Fienstein & Horowitz 1997).