Metabolic, health and lifestyle profiling of breast cancer radiotherapy patients and the risk of developing fatigue

Background: Fatigue is commonly reported by cancer patients. In some instances it can persist after treatment is com-pleted. In order to develop effective treatment strategies it is important to understand the mechanisms underlying the development of fatigue and to be able to predict those that may be at greatest risk of experiencing fatigue during and following treatment. The current paper examines predisposing factors for fatigue including altered fatty acid homeosta-sis in a cohort of breast cancer radiotherapy patients. Methodology: Patients had undergone breast-conserving surgery and adjuvant breast irradiation. Prior to radiotherapy the patients were free from significant fatigue. Levels of fatigue were determined prior to and following radiotherapy using the Functional Assessment of Cancer Therapy fatigue sub-scale. Plasma fatty acid levels, urinary and plasma amino acid levels, blood biochemistry factors and general health and lifestyle characteristics were assessed. Results: Following radiotherapy, significant fatigue affected approximately one third of the 26 patients and these subjects were then assigned to the fatigued cohort. Univariate analysis revealed that higher levels of the fatty acids myristic acid and eicosadienoic acid were present for the fatigued cohort prior to radio-therapy. Multivariate analysis also revealed that fatty acid homeostasis was altered between the fatigued and non-fatigued groups at baseline. Orthogonal partial least squares discriminant analysis of the general health, lifestyle and metabolic data revealed that the fatigued and non-fatigued patients could be clustered into two clearly separate groups. Conclusions: The results supported the proposition that the fatigued patients had an underlying metabolic ho-meostasis which may predispose them to the development of fatigue. Biochemical and general health profiling of breast cancer patients has the potential to identify those at most risk of developing significant fatigue following radiotherapy

Filterability of staphylococcal species through membrane filters following application of stressors

<p>Abstract</p> <p>Background</p> <p>Passage of bacterial cells through filter pores has been reported for a number of bacterial species. In this investigation, we tested the filterability of staphylococcal cultures that were exposed to several environmental stress conditions by passing them through 0.22 and 0.45 μm sterile filters, which are industry standards.</p> <p>Findings</p> <p>Results showed repeated passage of viable staphylococcal cells through both pore sizes, although more passage was seen through the 0.45 μm pore size. Of the three staphylococcal species, <it>S. lugdunensis </it>showed the best passage at relatively higher numbers regardless of the treatment, while both <it>S. aureus </it>and <it>S. epidermidis </it>showed limited passage or complete inhibition.</p> <p>Conclusion</p> <p>The data showed that staphylococcal bacteria were capable of passing through sterile filters in a viable state. There was better passage through 0.45 μm sterile filters than through the 0.22 μm sterile filters. Application of a stress condition did not appear to enhance filterability of these bacterial cultures.</p

Effect of Low Temperature on Growth and Ultra-Structure of Staphylococcus spp

The effect of temperature fluctuation is an important factor in bacterial growth especially for pathogens such as the staphylococci that have to remain viable during potentially harsh and prolonged transfer conditions between hosts. The aim of this study was to investigate the response of S. aureus, S. epidermidis, and S. lugdunensis when exposed to low temperature (4°C) for prolonged periods, and how this factor affected their subsequent growth, colony morphology, cellular ultra-structure, and amino acid composition in the non-cytoplasmic hydrolysate fraction. Clinical isolates were grown under optimal conditions and then subjected to 4°C conditions for a period of 8 wks. Cold-stressed and reference control samples were assessed under transmission electron microscopy (TEM) to identify potential ultra-structural changes. To determine changes in amino acid composition, cells were fractured to remove the lipid and cytoplasmic components and the remaining structural components were hydrolysed. Amino acid profiles for the hydrolysis fraction were then analysed for changes by using principal component analysis (PCA). Exposure of the three staphylococci to prolonged low temperature stress resulted in the formation of increasing proportions of small colony variant (SCV) phenotypes. TEM revealed that SCV cells had significantly thicker and more diffuse cell-walls than their corresponding WT samples for both S. aureus and S. epidermidis, but the changes were not significant for S. lugdunensis. Substantial species-specific alterations in the amino acid composition of the structural hydrolysate fraction were also observed in the cold-treated cells. The data indicated that the staphylococci responded over prolonged periods of cold-stress treatment by transforming into SCV populations. The observed ultra-structural and amino acid changes were proposed to represent response mechanisms for staphylococcal survival amidst hostile conditions, thus maintaining the viability of the species until favourable conditions arise again

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Small colony variants of staphylococci: pathogenesis and evolutionary significance in causing and sustaining problematic human infections

Background: Small colony variants have been implicated as the cause of several chronic disease states unmanageable by antibiotic therapy. Thus, this review evaluates the mechanisms employed by this subpopulation in the propagation of nosocomial infections involving the staphylococcal species. Furthermore, we propose several hypotheses for the evolutionary role this phenotype may play in clinical settings. Results: Research suggests that a combined effort of certain auxotrophies contributes to a reduced metabolic rate within small colony variant bacteria. This minimizes the effect of antibiotics used against them and allows this phenotype to endure as an intracellular infection. Additionally, numerous studies have suggested that perhaps these variants alter the mechanisms of the immune system that are normally fashioned against such invasive pathogens. Studies have shown that although these variants possess reduced virulence factors compared with parental strains, they exhibit an increased ability to attach and colonize intracellularly in the host cells, making eradication difficult. Conclusions: The formation of a small colony variant phenotype has been found to be a vital mode of existence for nosocomial bacteria, as it offers numerous survival options without expending valuable metabolic resources while sustaining severe chronic infections. It is suggested that intracellular survivability is the major role played by this variant. There is a need to develop clinical techniques that will be sensitive for the rapid detection and diagnosis of these variant populations. Ultimately, understanding the survival mechanisms used by these variants is imperative for the administration of suitable treatment regimens

Extensive bacterial diversity indicates the potential operation of a dynamic micro-ecology within domestic rainwater storage systems

The concept that domestic rainwater storage tanks may host sustainable microbial ecosystems has not previously been addressed. The bacterial diversity, cultivated from more than 80 samples from 22 tanks at various locations across eastern Australia, is presented here as prima facie evidence for the potential operation of a functional micro-ecology within rainwater storage systems. Cultivated isolates were found to comprise members of four major bacterial divisions; Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes, including more than 200 species from 80 different genera. The pattern of abundance distribution was typical of that observed in most natural communities, comprising a small number of abundant taxa and a multitude of rare taxa, while the specific composition resembled that previously described in a number of natural aquatic systems. Although Proteobacteria from α, β and γ sub-classes were dominant, a set of core taxa comprising representative genera from all four phyla could be identified. Coliform and other species specifically associated with faecal material comprised <15% of the species identified, and represented <1.5% of total average abundance. The composition of the cultivated populations and scope of diversity present, suggested that rainwater tanks may support functional ecosystems comprising complex communities of environmental bacteria, which may have beneficial implications for the quality of harvested rainwater

Effect of the pollutants lead, zinc, hexadecane and octocosane on total growth and shell growth in the Akoya pearl oyster, Pinctada imbricata

Pearl oysters (Pinctada imbricata) were held in the laboratory and exposed to various levels of the heavy metals lead and zinc and the aliphatic hydrocarbons hexadecane and octacosane for 2 months. Individual oysters were followed over the course of the experiment, allowing specific calculation of total oyster growth (wet weight) and shell growth. Significant reductions in total oyster growth were observed when oysters were exposed to high concentrations (270μg L^-1) of either zinc or lead. Exposure to the aliphatic hydrocarbons had no effect on total oyster growth. High concentrations of lead completely halted shell growth, the first demonstration of pollutant induced cessation of biomineralization in pearl oysters. Conversely, exposure to moderate levels of lead and the long-chain hydrocarbon octacosane resulted in significant increases in shell width growth. The results from this study indicate that P. imbricata is relatively tolerant of the selected pollutants and could be deployed within a remediative context in moderately polluted coastal areas

Changes in abundance of heterotrophic and coliform bacteria resident in stored water bodies in relation to incoming bacterial loads following rain events

Microbial properties of harvested rainwater were assessed at two study sites at Newcastle on the east coast of Australia. The investigation monitored daily counts of heterotrophic bacteria (HPC), total coliforms and E. coli during a mid-winter month (July). Immediately after a major rainfall event, increases in bacterial loads were observed at both sites, followed by gradual reductions in numbers to prior baseline levels within 7 days. Baseline HPC levels ranged from 500–1000 cfu/mL for the sites evaluated, and the loads following rain peaked at 3590–6690 cfu/mL. Baseline levels of total coliforms ranged from 0–100 cfu/100 mL and peaked at 480–1200 cfu/100 mL following rain. At Site 1, there was no evidence of E. coli loading associated with the rain events assessed, and Site 2 had no detectable E. coli colonies at baseline, with a peak load of 17 cfu/100 mL following rain which again diminished to baseline levels. It was concluded that rainfall events contributed to the bacterial load in rainwater storage systems, but processes within the rainwater storage ensured these incoming loads were not sustained

Rainwater quality from roofs, tanks and hot water systems at Figtree Place

Figtree Place is a water sensitive urban redevelopment consisting of 27 residential units located in Hamilton, an inner suburb of Newcastle, NSW, Australia. The site uses rainwater stored in tanks to supply hot water and toilet flushing demand. A two-year monitoring program for roofwater, tanks and hot water systems revealed that water quality improves in the roof to tank to hot water system treatment chain. Analysis of water quality from hot water systems and rainwater tanks showed compliance with the Australian Drinking Water Guidelines