Mapping the pathways to staphylococcal pathogenesis by comparative secretomics.

The gram-positive bacterium Staphylococcus aureus is a frequent component of the human microbial flora that can turn into a dangerous pathogen. As such, this organism is capable of infecting almost every tissue and organ system in the human body. It does so by actively exporting a variety of virulence factors to the cell surface and extracellular milieu. Upon reaching their respective destinations, these virulence factors have pivotal roles in the colonization and subversion of the human host. It is therefore of major importance to obtain a clear understanding of the protein transport pathways that are active in S. aureus. The present review aims to provide a state-of-the-art roadmap of staphylococcal secretomes, which include both protein transport pathways and the extracytoplasmic proteins of these organisms. Specifically, an overview is presented of the exported virulence factors, pathways for protein transport, signals for cellular protein retention or secretion, and the exoproteomes of different S. aureus isolates. The focus is on S. aureus, but comparisons with Staphylococcus epidermidis and other gram-positive bacteria, such as Bacillus subtilis, are included where appropriate. Importantly, the results of genomic and proteomic studies on S. aureus secretomes are integrated through a comparative "secretomics" approach, resulting in the first definition of the core and variant secretomes of this bacterium. While the core secretome seems to be largely employed for general housekeeping functions which are necessary to thrive in particular niches provided by the human host, the variant secretome seems to contain the "gadgets" that S. aureus needs to conquer these well-protected niches.     

Mapping the Pathways to Staphylococcal Pathogenesis by Comparative Secretomics

The gram-positive bacterium Staphylococcus aureus is a frequent component of the human microbial flora that can turn into a dangerous pathogen. As such, this organism is capable of infecting almost every tissue and organ system in the human body. It does so by actively exporting a variety of virulence factors to the cell surface and extracellular milieu. Upon reaching their respective destinations, these virulence factors have pivotal roles in the colonization and subversion of the human host. It is therefore of major importance to obtain a clear understanding of the protein transport pathways that are active in S. aureus. The present review aims to provide a state-of-the-art roadmap of staphylococcal secretomes, which include both protein transport pathways and the extracytoplasmic proteins of these organisms. Specifically, an overview is presented of the exported virulence factors, pathways for protein transport, signals for cellular protein retention or secretion, and the exoproteomes of different S. aureus isolates. The focus is on S. aureus, but comparisons with Staphylococcus epidermidis and other gram-positive bacteria, such as Bacillus subtilis, are included where appropriate. Importantly, the results of genomic and proteomic studies on S. aureus secretomes are integrated through a comparative “secretomics” approach, resulting in the first definition of the core and variant secretomes of this bacterium. While the core secretome seems to be largely employed for general housekeeping functions which are necessary to thrive in particular niches provided by the human host, the variant secretome seems to contain the “gadgets” that S. aureus needs to conquer these well-protected niches.     

Proposed follow up programme after curative resection for lower third oesophageal cancer

Cyclins are indispensable elements of the cell cycle and derangement of their function can lead to cancer formation. Recent studies have also revealed more mechanisms through which cyclins can express their oncogenic potential. This review focuses on the aberrant expression of G1/S cyclins and especially cyclin D and cyclin E; the pathways through which they lead to tumour formation and their involvement in different types of cancer. These elements indicate the mechanisms that could act as targets for cancer therapy.     

Consistency of side choice in the milking parlour by Holstein-Friesian cows and its relationship with their reactivity and milk yield

Dairy cows often have to choose which of two sides to enter in the milking parlour. Some cows are very consistent in this choice, and it is common to assume that when these cows are more disturbed are being milked in their non-preferred side. Such disturbance might involve significantly poor welfare. In order to assess this assumption, we decided to study the behaviour and milk yield of dairy cows and their relationships with side preference in the milking parlour. The study was carried out at Cambridge University Farm, in a two-sided tandem milking parlour. The data collection followed the daily management routine. We recorded the side chosen by each cow (left or right) during 40 milking sessions. Data from 70 cows, which were present in at least 25 milking sessions (mode=36), were included in the statistical analysis. Cows' reactivity (CR) during premilking udder preparation, time spent fitting the milking cluster (FT), milk yield (MY) and duration of milking (DM) were measured. There was evident individual variation in the consistency of side choice. Individual differences (ANOVA, P<0.001) were also found in CR, FT, MY and DM; although these variables were not significantly affected by the side or the interaction animalxside (ANOVA, P>0.05). The comparison between left and right side means (paired t-test) of these variables did not show significant differences (P>0.05). We concluded that there is no evidence that the cows were discomforted or stressed when milked in the non-preferred side of the milking parlour.     

Comparative morphology of the sagittal otolith in Serranus spp.

Variations in the morphology of saccular otoliths (sagittae) among three sympatric species of the genus Serranus ( S. atricauda , S. cabrilla and S. scriba ) from the Canary Islands were investigated. Although the otolith gross morphology was similar among species, S. scriba was distinct in having a rostrum which had a slight turning at the tip and a more funnel‐like ostium. The shallower water species ( S. scriba ) had otolith and sulcus areas which were smaller than the deeper water species ( S. cabrilla and S. atricauda ). The sulcus acusticus and ostium size were correlated with the habit depth of the species, with the highest values in the deepest species, S. cabrilla . The otolith outline shape indices changed with size (total length) of the species, and allowed the separation of the species by means of a discriminate function.     

Effects of space allowance on the grazing behaviour and spacing of sheep

In each of two experiments, four groups of 10 female Scottish Blackface sheep grazed for 2 weeks at each of four space allowances, according to a Greco-Latin Square design. Space allowances were 80, 100, 133 or 200m(2) per head in Experiment 1 and 50, 67, 100 or 200m(2) per head in Experiment 2. Confounding of space allowance and grazing pressure was avoided by the use of a rotational grazing system. Mean distances between sheep were measured from video recordings and distances expected by chance were calculated from simulations in which sheep were located within plot areas using randomly selected co-ordinates.Total time spent grazing was higher at 200m(2) per head and less at 50m(2) per head than at other space allowances, but there was no evidence for an effect of space allowance on herbage intake or digestibility, biting rate or the proportion of grazing time spent in ingestive behaviour. At space allowances from 50 to 133m(2) per head, there were no significant differences between mean observed inter-animal distances and those expected by chance, but observed values were lower than expected values at 200m(2) per head. At all space allowances, mean observed distances between sheep and their nearest neighbours were lower than distances expected by chance.The results show that, on relatively high quality, homogeneous vegetation, female Scottish Blackface sheep will graze at space allowances between 50 and 200m(2) per animal with no evidence of repulsion between individuals and with no clear evidence of grouping until space allowance reaches 200m(2). It is concluded that the relationship between grazing time and space allowance may reflect the extra activity required to maintain group cohesion as space allowance increases.     

Distribution of mental health professionals working on site in English and Welsh general practices.

OBJECTIVE--To describe the nature and distribution of mental health professionals working on site in general practices. DESIGN--Postal questionnaire and telephone interview survey. SETTING--English and Welsh general practices. SUBJECTS--1880 general practitioners, of whom 1542 (82%) responded. MAIN OUTCOME MEASURES--Prevalence, types, and distribution of mental health professionals working on site among general practices. Factors predicting the presence of mental health professionals on site. RESULTS--The number of practices reporting the presence on site of each type of professional were 528 for community psychiatric nurses; 266 for practice counsellors; 177 for clinical psychologists; 132 for psychiatrists; 96 for psychiatric social workers; and 45 for psychotherapists. Mental health professionals tended to cluster together in practices more often than expected by chance alone. Practice characteristics which independently predicted the presence of a mental health professional on site were having four or more partners; being a training practice; and running stress, bereavement, or other mental health clinics. The proportions of practices with mental health professionals on site varied significantly among health regions. There was no association between the presence of mental health professionals on site and the location of practices, the social class mix of patients, or the estimated percentage of elderly patients or patients of non-European origin. CONCLUSIONS--Mental health professionals tend to cluster together, with a preponderance in larger training practices. Specialist mental health care provision within general practices is unevenly distributed. Further research is needed to determine whether this uneven distribution reflects differences in need or inequalities in the provision of mental health services.     

Duodenal mucosal risk markers in patients with familial adenomatous polyposis: effects of celecoxib/ursodeoxycholic acid co-treatment and comparison with patient controls

Background

Familial adenomatous polyposis (FAP) is a disease characterized by the development of hundreds to thousands of adenomatous polyps in the colorectum early in life. Virtually all patients with FAP will develop colorectal cancer before the age of 40 to 50 years, unless prophylactic colectomy is performed, which significantly improves their prognosis. The mortality pattern has changed and duodenal cancer now is one of the main cancer-related causes of death in these patients. Practically all patients with FAP develop premalignant duodenal adenomas, which may develop to duodenal cancer in approximately 3-7% of patients. Duodenal cancer in patients with FAP has a poor prognosis. The clinical challenge is to identify patients at high-risk for duodenal carcinoma. Chemoprevention would be desirable to avoid duodenectomy. The main goal of this study is to identify risk markers in normal duodenal mucosa of patients with FAP, that could help identify patients at increased risk for malignant transformation.

Methods

Messenger RNA (mRNA) levels of glutathione S-transferase A1 (GSTA1), glutathione S-transferase P1 (GSTP1), KIAA1199, E-cadherin, peroxisome proliferative activated receptor δ (PPARδ), caspase-3, cyclin D1, β-catenin, and cyclooxygenase-2 (COX-2) were measured in duodenal mucosa, using the QuantiGene 2.0 Plex assay. Levels in normal appearing mucosa of patients with FAP (n?=?37) were compared with levels in non-FAP patient controls (n?=?16). In addition, levels before and after treatment with either celecoxib & ursodeoxycholic acid (UDCA, n?=?14) or celecoxib & placebo (n?=?13) were evaluated in patients with FAP.

Results

mRNA levels of glutathione S-transferase A1 (28.16% vs. 38.24%, p?=?0.008) and caspase-3 (3.30% vs. 5.31%, p?=?0.001) were significantly lower in patients with FAP vs. non-FAP patient controls, respectively. COX-2 mRNA levels in normal duodenal mucosa of patients with FAP were found to be unexpectedly low. None of the potential risk markers was influenced by celecoxib or celecoxib & UDCA.

Conclusions

Protection against toxins and carcinogens (GSTA1) and apoptosis (caspase-3) is low in patients with FAP, which could contribute to increased susceptibility for malignant transformation of duodenal mucosa.

Trial registration

http://ClinicalTrials.gov number NCT00808743