Effects of phosphates on Pseudomonas fragi growth, protease production and activity

The antimicrobial effects of selected inorganic phosphates on the growth of Pseudomonas fragi and protease activity in synthetic medium and in ground pork were studied. Studies were designed to determine the antimicrobial effects of phosphates at concentrations allowed in meat products and at concentrations above this limit. Microbial growth was monitored by traditional antimicrobial tests including the agar dilution method and liquid medium kill curve method. Protease activity was evaluated based on a casein digestion method and was reported per organism or per mg protein. At phosphate concentrations allowed by regulation in a meat product, the phosphates were not found to be inhibitory to growth or protease activity. However, concentrations greater than 0.5% were found to be inhibitory to P. fragi growth and to the synthesis of the protease

Irinotecan pharmacogenomics

Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the majority of evidence to date suggests that variation in expression of UGT1A1 caused by a common promoter polymorphism (UGT1A1*28) is strongly associated with toxicity; however, this link is dose dependent. Variations in other pharmacokinetic genes, particularly the transporter ABCC2, also contribute to irinotecan toxicity. In addition, recent studies have shown that pharmacodynamic genes such as TDP1 and XRCC1 can also play a role in both toxicity and response

DNA methylotype analysis in colorectal cancer

The methylation status of a gene promoter is considered to be an important mechanism for the development of many tumors, including colorectal cancer. Recent studies have shown that specific patterns of DNA methylation across multiple CpG loci in some human tumors are more informative than the detection of one single CpG locus in tumor genomes. In the present study, multiple CpG methylations of three genes (CDKN2A, DPYD and MLH1) were detected in DNA samples from patients with colorectal cancer using Pyrosequencing(®) technology. The bisulfite-converted DNA was amplified with a nested PCR and five or six CpG loci of each gene were assessed to determine DNA methylotype. Our data showed that 10/49 (20.4%), 6/48 (12.5%) and 14/49 (28.6%) of tumors were methylated with a DNA methylation level >0.2 in CDKN2A, DPYD and MLH1, respectively. Our study indicated a similar DNA methylation level across the multiple CpG loci for all three genes in the methylated tumor DNA samples, demonstrating a dichotomous trait in DNA methylation. The tumor DNA samples had unique DNA methylation patterns, which were high-degree and multiple-site methylation, but the normal DNA samples had no or a low-degree and dispersed single-site methylation. In addition, an inverse correlation in those methylated tumors was observed between DNA methylation and RNA expression for MLH1 (R(S)=−0.62, P=0.003), but not for CDKN2A and DPYD. In conclusion, distinctive DNA methylotypes exist in colorectal cancer and may depict a distinct biology in apparently homogeneous tumors

Impact of the ‘Contributing Factors in Construction Accidents’ (ConCA) model

In 2005 the ‘Contributing factors in Construction Accidents’ framework (ConCA) introduced a sociotechnical systems approach to risk management in construction. ConCA demonstrated the value of exploring distal factors and identifying underlying or latent causes: It promoted an understanding of construction accidents as systemic accidents and challenged an industry-wide culture of blaming frontline workers. A decade later the original article has been cited by research from 37 countries, shaping inquiries and initiatives to improve safety in both the UK and Australia. But to what extent has systems thinking infiltrated practitioners and policy-makers’ views? Despite broader views of contributing factors, many practitioners still view workers in a negative light, holding them responsible for accidents because of complacency, cynicism about safety, or a high-tolerance for risk. This paper evaluates the impact of the ConCA framework, updates it, and develops our understanding of the relationships between immediate circumstances and distal factors, as seen by an expert panel of participants (n = 32). A more in-depth ‘ConCA+’ framework is proposed. It challenges the negative perceptions of workers, and supports shifting the emphasis of risk management away from worker behaviors and towards resolving wider systemic issues. New directions are proposed which show how knowledge management, job design, technological innovation, empowerment and collaboration should be the focus of future work

A Phase II Study of Irinotecan and Carboplatin in Advanced Non-small Cell Lung Cancer with Pharmacogenomic Analysis: Final Report

PurposeWe conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity.Patients and MethodsPatients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1).ResultsForty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia (p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes (p = 0.057).ConclusionThe combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity

Efficacy and acceptability of pharmacological and non-pharmacological interventions for non-specific chronic low back pain:a protocol for a systematic review and network meta-analysis

Background: Despite the enormous financial and humanistic burden of chronic low back pain (CLBP), there is little consensus on what constitutes the best treatment options from a multitude of competing interventions. The objective of this network meta-analysis (NMA) is to determine the relative efficacy and acceptability of primary care treatments for non-specific CLBP, with the overarching aim of providing a comprehensive evidence base for informing treatment decisions. Methods: We will perform a systematic search to identify randomised controlled trials of interventions endorsed in primary care guidelines for the treatment of non-specific CLBP in adults. Information sources searched will include major bibliographic databases (MEDLINE, Embase, CENTRAL, CINAHL, PsycINFO and LILACS) and clinical trial registries. Our primary outcomes will be patient-reported pain ratings and treatment acceptability (all-cause discontinuation), and secondary outcomes will be functional ability, quality of life and patient/physician ratings of overall improvement. A hierarchical Bayesian class-based NMA will be performed to determine the relative effects of different classes of pharmacological (NSAIDs, opioids, paracetamol, anti-depressants, muscle relaxants) and non- pharmacological (exercise, patient education, manual therapies, psychological therapy, multidisciplinary approaches, massage, acupuncture, mindfulness) interventions and individual treatments within a class (e.g. NSAIDs: diclofenac, ibuprofen, naproxen). We will conduct risk of bias assessments and threshold analysis to assess the robustness of the findings to potential bias. We will compute the effect of different interventions relative to placebo/no treatment for both short- and long-term efficacy and acceptability. Discussion: While many factors are important in selecting an appropriate intervention for an individual patient, evidence for the analgesic effects and acceptability of a treatment are key factors in guiding this selection. Thus, this NMA will provide an important source of evidence to inform treatment decisions and future clinical guidelines

SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase

Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity