Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer : diagnostic and therapeutic potential

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC

The bacterial symbiont Phaeobacter inhibens Shapes the life history of its algal host emiliania huxleyi

© 2018 Bramucci, Labeeuw, Orata, Ryan, Malmstrom and Case. Marine microbes form host-associated biofilm communities that are shaped by complex interactions between bacteria and their host. The roseobacter Phaeobacter inhibens exploits both symbiotic and pathogenic niches while interacting with its microalgal host Emiliania huxleyi. During co-cultivation over extended periods with E. huxleyi, we show that P. inhibens selectively kills two host cell types, the diploid calcifying strain and the haploid flagellated strain. Meanwhile, various non-calcifying diploid strains are resistant to this pathogen or the pathogen is avirulent to this cell type. This differential pathogenesis has the potential of dramatically altering the composition of E. huxleyi blooms, which are typically dominated by the roseobacter-susceptible calcifying strain. This cell type makes calcite plates, which are an important sink in the marine carbon cycle and forms part of the marine paleobotanic record. P. inhibens kills the haploid cells, which have been proposed as critical to the survival of the algae, as they readily escape both eukaryotic predation and viral infection. Consequently, bacteria such as P. inhibens could influence E. huxleyi's life history by selective pathogenesis, thereby altering the composition of cell types within E. huxleyi populations and its bloom-bust lifestyle

Investigating The Life Cycle Of Haplosporidium nelsoni (MSX)

Attempts to decipher the life cycle of Haplosporidium nelsoni began almost immediately after it was identified as the pathogen causing MSX disease in eastern oysters, Crassostrea virginica. But transmission experiments failed and the spore stage, characteristic of haplosporidans, was extremely rare. Researchers concluded that another host was involved: an intermediate host in which part of the life cycle was produced, or-if the oyster was an accidental host-an alternate host that produces infective elements. A later finding that spores were found more often in spat (\u3c 1 y old) than in adults revived the idea of direct transmission between oysters. The new findings and the availability of molecular diagnostics led us to revive life cycle investigations. Over several years, oyster spat were examined for spores and searched for H. nelsoni in potential non-oyster hosts using both histological and polymerase chain reaction (PCR) methodologies. Although spores occurred in a high proportion of spat with advanced infections, it was concluded that they were unlikely to be a principal source of infective elements because naive oysters used as sentinels to assess infection pressure became highly infected even after native oysters developed resistance, and infected spat could no longer be found. A histological survey of zooplankton and small bivalves in Delaware Bay found few recognizable parasites and nothing resembling a haplosporidan. A subsequent PCR study of water, sediment, and macro-invertebrates from Chesapeake, Delaware, and Oyster bays resulted in many positive samples, but in situ hybridization failed to identify any recognizable structures. PCR analysis of potential intermediate hosts for other molluscan pathogens has also resulted in many species yielding positive results but required in situ hybridization to verify infections. It is suggested that any future search for a nonoyster host of H. nelsoni be conducted in a relatively confined system and/or target specific phyla, strategies that have been successful in other life cycle studies. It is noted that candidate phyla could include those known to host haplosporidans and species whose abundance or distribution may have changed in concert with outbreaks of MSX disease in the northeastern United States in recent years

RepSeq-A database of amino acid repeats present in lower eukaryotic pathogens

BACKGROUND Amino acid repeat-containing proteins have a broad range of functions and their identification is of relevance to many experimental biologists. In human-infective protozoan parasites (such as the Kinetoplastid and Plasmodium species), they are implicated in immune evasion and have been shown to influence virulence and pathogenicity. RepSeq http://repseq.gugbe.com is a new database of amino acid repeat-containing proteins found in lower eukaryotic pathogens. The RepSeq database is accessed via a web-based application which also provides links to related online tools and databases for further analyses. RESULTS The RepSeq algorithm typically identifies more than 98% of repeat-containing proteins and is capable of identifying both perfect and mismatch repeats. The proportion of proteins that contain repeat elements varies greatly between different families and even species (3 - 35% of the total protein content). The most common motif type is the Sequence Repeat Region (SRR) - a repeated motif containing multiple different amino acid types. Proteins containing Single Amino Acid Repeats (SAARs) and Di-Peptide Repeats (DPRs) typically account for 0.5 - 1.0% of the total protein number. Notable exceptions are P. falciparum and D. discoideum, in which 33.67% and 34.28% respectively of the predicted proteomes consist of repeat-containing proteins. These numbers are due to large insertions of low complexity single and multi-codon repeat regions. CONCLUSION The RepSeq database provides a repository for repeat-containing proteins found in parasitic protozoa. The database allows for both individual and cross-species proteome analyses and also allows users to upload sequences of interest for analysis by the RepSeq algorithm. Identification of repeat-containing proteins provides researchers with a defined subset of proteins which can be analysed by expression profiling and functional characterisation, thereby facilitating study of pathogenicity and virulence factors in the parasitic protozoa. While primarily designed for kinetoplastid work, the RepSeq algorithm and database retain full functionality when used to analyse other species

Opinion leaders and changes over time: a survey

<p>Abstract</p> <p>Background</p> <p>Opinion leaders represent one way to disseminate new knowledge and influence the practice behaviors of physicians. This study explored the stability of opinion leaders over time, whether opinion leaders were polymorphic (<it>i.e.</it>, influencing multiple practice areas) or monomorphic (<it>i.e.</it>, influencing one practice area), and reach of opinion leaders in their local network.</p> <p>Methods</p> <p>We surveyed surgeons and pathologists in Ontario to identify opinion leaders for colorectal cancer in 2003 and 2005 and to identify opinion leaders for breast cancer in 2005. We explored whether opinion leaders for colorectal cancer identified in 2003 were re-identified in 2005. We examined whether opinion leaders were considered polymorphic (nominated in 2005 as opinion leaders for both colorectal and breast cancer) or monomorphic (nominated in 2005 for only one condition). Social-network mapping was used to identify the number of local colleagues identifying opinion leaders.</p> <p>Results</p> <p>Response rates for surgeons were 41% (2003) and 40% (2005); response rates for pathologists were 42% (2003) and 37% (2005). Four (25%) of the surgical opinion leaders identified in 2003 for colorectal cancer were re-identified in 2005. No pathology opinion leaders for colorectal cancer were identified in both 2003 and 2005. Only 29% of surgical opinion leaders and 17% of pathology opinion leaders identified in the 2005 survey were considered influential for both colorectal cancer and breast cancer. Social-network mapping revealed that only a limited number of general surgeons (12%) or pathologists (7%) were connected to the social networks of identified opinion leaders.</p> <p>Conclusions</p> <p>Opinion leaders identified in this study were not stable over a two-year time period and generally appear to be monomorphic, with clearly demarcated areas of expertise and limited spheres of influence. These findings may limit the practicability of routinely using opinion leaders to influence practice.</p

Serum Neurofilament Light is elevated in COVID-19 Positive Adults in the ICU and is associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch's t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch's t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status

Survey of the needs of patients with spinal cord injury: impact and priority for improvement in hand function in tetraplegics\ud

Objective: To investigate the impact of upper extremity deficit in subjects with tetraplegia.\ud \ud Setting: The United Kingdom and The Netherlands.\ud \ud Study design: Survey among the members of the Dutch and UK Spinal Cord Injury (SCI) Associations.\ud \ud Main outcome parameter: Indication of expected improvement in quality of life (QOL) on a 5-point scale in relation to improvement in hand function and seven other SCI-related impairments.\ud \ud Results: In all, 565 subjects with tetraplegia returned the questionnaire (overall response of 42%). Results in the Dutch and the UK group were comparable. A total of 77% of the tetraplegics expected an important or very important improvement in QOL if their hand function improved. This is comparable to their expectations with regard to improvement in bladder and bowel function. All other items were scored lower.\ud \ud Conclusion: This is the first study in which the impact of upper extremity impairment has been assessed in a large sample of tetraplegic subjects and compared to other SCI-related impairments that have a major impact on the life of subjects with SCI. The present study indicates a high impact as well as a high priority for improvement in hand function in tetraplegics.\ud \u

Funding models in palliative care: lessons from international experience

Background:Funding models influence provision and development of palliative care services. As palliative care integrates into mainstream health care provision, opportunities to develop funding mechanisms arise. However, little has been reported on what funding models exist or how we can learn from them.Aim:To assess national models and methods for financing and reimbursing palliative care.Design:Initial literature scoping yielded limited evidence on the subject as national policy documents are difficult to identify, access and interpret. We undertook expert consultations to appraise national models of palliative care financing in England, Germany, Hungary, Republic of Ireland, New Zealand, The Netherlands, Norway, Poland, Spain, Sweden, Switzerland, the United States and Wales. These represent different levels of service development and a variety of funding mechanisms.Results:Funding mechanisms reflect country-specific context and local variations in care provision. Patterns emerging include the following:Provider payment is rarely linked to population need and often perpetuates existing inequitable patterns in service provision.Funding is frequently characterised as a mixed system of charitable, public and private payers.The basis on which providers are paid for services rarely reflects individual care input or patient needs.Conclusion:Funding mechanisms need to be well understood and used with caution to ensure best practice and minimise perverse incentives. Before we can conduct cross-national comparisons of costs and impact of palliative care, we need to understand the funding and policy context for palliative care in each country of interest