Environmental, lifestyle, and familial/ethnic factors associated with myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are characterized by overproduction of mature functional blood cells and are often associated with an acquired genetic mutation of Janus Kinase 2V617F. The etiology of MPNs remains unknown. The aim of this article was to review and collate all known published data investigating environmental and lifestyle factors associated with MPNs. Medline, Embase, PubMed, Cochrane, and Web of Science were systematically searched using terms for MPNs and observational study designs to identify studies investigating the risk factors for MPNs published before March 2010. Of 9,156 articles identified, 19 met the selection criteria. Although the studies exhibited heterogeneity, in case definitions, study design, and risk factors investigated, several themes emerged. A strong association was found with Jewish descent, and with a family history of MPNs. Autoimmune conditions, specifically Crohn's disease, were more common in patients with MPNs. Certain occupational groups were significantly associated with MPNs including occupations with potential exposure to benzene and/or petroleum. Blood donation was associated with an increased risk of polycythemia vera specifically. The vast heterogeneity in studies identified as part of this review suggests that large scale systematic assessment of etiological factors associated with MPNs is warranted. (C) 2011 Wiley-Liss, Inc.

EURODIAB childhood type 1 diabetes incidence registers - results from the first 20 years. Oral presentation at the 47th EASD Annual Meeting, Lisbon, Portugal.

Background and aims: In 1989 a number of registers in Europe began recording new cases of type 1 diabetes diagnosed in children aged under 15 years using a common protocol. Trends in incidence rate during the 20 year period 1989-2008 are described.
Materials and methods: All registers operate in geographically defined regions and are based on a clinical diagnosis. When possible, completeness of registration in each register is assessed using capture-recapture methodology by identifying primary and secondary sources of ascertainment. The completeness estimate is obtained by identifying the numbers of cases identified by the primary source only, by the secondary source only and by both the primary and the secondary sources.
Results: Other registers have joined the Group since 1989, and 21 registers in 15 countries continue to submit registration data. In the first five years (1989-93) incidence rates varied from 3.2 per 100,000 in the Former Yugoslav Republic of Macedonia to 25.8 per 100,000 in the Stockholm area of Sweden. In the last five years (2004-2008) these same two registers again had the lowest and highest incidence, but rates had increased to 5.8 per 100,000 and 36.6 per 100,000, respectively. During the 20 year period all but two of the 21 registers showed statistically significant rates of increase (median rate of increase 4% per annum), and similar figures were obtained when this median rate of increase was estimated for the first half of the period (1989-98) and for the second half (1999-2008) . However, rates of increase differed significantly between the first half and the second half of the period for eight of the 17 registers with adequate coverage of both periods; four registers showing significantly higher rates of increase in the first half and four significantly higher rates in the second half.
Conclusion: The childhood type 1 diabetes incidence rate continues to rise across Europe by approximately 4% per annum, but the increase within a register is not necessarily uniform with periods of less rapid and more rapid increase in incidence occurring in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions are warranted.

The importance of solid-phase distribution on the oral bioaccessibility of Ni and Cr in soils overlying Palaeogene basalt lavas, Northern Ireland

Potentially toxic elements (PTEs) including nickel and chromium are often present in soils overlying basalt at concentrations above regulatory guidance values due to the presence of these elements in underlying geology. Oral bioaccessibility testing allows the risk posed by PTEs to human health to be assessed; however, bioaccessibility is controlled by factors including mineralogy, particle size, solid-phase speciation and encapsulation. X-ray diffraction was used to characterise the mineralogy of 12 soil samples overlying Palaeogene basalt lavas in Northern Ireland, and non-specific sequential extraction coupled with chemometric analysis was used to determine the distribution of elements amongst soil components in 3 of these samples. The data obtained were related to total concentration and oral bioaccessible concentration to determine whether a relationship exists between the overall concentrations of PTEs, their bioaccessibility and the soils mineralogy and geochemistry. Gastric phase bioaccessible fraction (BAF %) ranged from 0.4 to 5.4 % for chromium in soils overlying basalt and bioaccessible and total chromium concentrations are positively correlated. In contrast, the range of gastric phase BAF for nickel was greater (1.4–43.8 %), while no significant correlation was observed between bioaccessible and total nickel concentrations. However, nickel BAF was inversely correlated with total concentration. Solid-phase fractionation information showed that bioaccessible nickel was associated with calcium carbonate, aluminium oxide, iron oxide and clay-related components, while bioaccessible chromium was associated with clay-related components. This suggests that weathering significantly affects nickel bioaccessibility, but does not have the same effect on the bioaccessibility of chromium.

Proper expression of the O-antigen of lipopolysaccharide is essential for the virulence of Yersinia enterocolitica O:8 in experimental oral infection of rabbits

The O-antigen of lipopolysaccharide (LPS) is required for virulence in Yersinia enterocolitica serotype O:8. Here we evaluated the importance of controlling the O-antigen biosynthesis using an in vivo rabbit model of infection. Y. enterocolitica O:8 wild-type strain was compared to three mutants differing in the O-antigen phenotype: (i) the rough strain completely devoid of the O-antigen, (ii) the wzy strain that lacks the O-antigen polymerase (Wzy protein) and expresses LPS with only one repeat unit, and (iii) the wzz strain that lacks the O-antigen chain length determinant (Wzz protein) and expresses LPS without modal distribution of O-antigen chain lengths. The most attenuated strain was the wzz mutant. The wzz bacteria were cleared from the tissues by day 30, the blood parameters were least dramatic and histologically only immunomorphological findings were seen. The level of attenuation of the rough and the wzy strain bacteria was between the wild-type and the wzz strain. Wild-type bacteria were highly resistant to killing by polymorphonuclear leukocytes, the wzz strain bacteria were most sensitive and the rough and wzy strain bacteria were intermediate resistant. These results clearly demonstrated that the presence of O-antigen on the bacterial surface is not alone sufficient for full virulence, but also there is a requirement for its controlled chain length.

Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations

Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 13%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.

Oral prednisone in guarded filtration procedures supplemented with antimetabolites

BACKGROUND AND OBJECTIVE: To evaluate whether a three-day course of oral prednisone perioperatively improves the surgical outcome of guarded filtering procedures supplemented with antifibrosis agents. DESIGN, MATERIALS AND METHODS: A prospective, randomized, double-masked, placebo-controlled, clinical trial was designed. Adult patients with non-inflammatory glaucoma undergoing a guarded filtration procedure supplemented with antimetabolite were enrolled. Patients received a three-day course of prednisone (50 mg BID) or placebo perioperatively. The main outcome measures were intraocular pressure (IOP) and number of antiglaucoma medications. Surgical success was defined before data collection according to two different criteria: 'success- I': IOP level = 15 mmHg with no more than one anti-glaucoma medication, and 'success-II': IOP reduction of at least 20% of baseline level with no more than one antiglaucoma medication. RESULTS: Thirty-five subjects were enrolled. Seventeen patients were treated with prednisone and eighteen with placebo. Mean follow-up was 9.2 months ± 6.2 months. The probability of success-I at 9 months was 63.0% in the study group and 65.6% in the control groups (p>0.05). The probability of success-II at 9 months was 60.2% in the study group and 55.0% in the control groups, (p>0.05). The difference in frequency of postoperative complications between groups was not statistically significant. The most common complication was choroidal detachment (n=2) in the prednisone-treated group and bleb leak (n=2) in the control group. CONCLUSION: The perioperative use of oral prednisone did not alter the surgical outcome of filtering procedures associated with antifibrosis agents in this population of glaucoma patients.

Development of novel oral formulations prepared via hot melt extrusion for targeted delivery of photosensitizer to the colon

Colon-residing bacteria, such as vancomycin-resistant Enterococcus faecalis and Bacteroides fragilis, can cause a range of serious clinical infections. Photodynamic antimicrobial chemotherapy (PACT) may be a novel treatment option for these multidrug resistant organisms. The aim of this study was to formulate a Eudragit®-based drug delivery system, via hot melt extrusion (HME), for targeting colonic release of photosensitizer. The susceptibility of E. faecalis and B. fragilis to PACT mediated by methylene blue (MB), meso-tetra(N-methyl-4-pyridyl)porphine tetra-tosylate (TMP), or 5-aminolevulinic acid hexyl-ester (h-ALA) was determined, with tetrachlorodecaoxide (TCDO), an oxygen-releasing compound, added in some studies. Results show that, for MB, an average of 30% of the total drug load was released over a 6-h period. For TMP and h-ALA, these values were 50% and 16% respectively. No drug was released in the acidic media. Levels of E. faecalis and B. fragilis were reduced by up to 4.67 and 7.73 logs, respectively, on PACT exposure under anaerobic conditions, with increased kill associated with TCDO. With these formulations, photosensitizer release could potentially be targeted to the colon, and colon-residing pathogens killed by PACT. TCDO could be used in vivo to generate oxygen, which could significantly impact on the success of PACT in the clinic.