Trends in corneal transplant surgery in Ireland: indications and outcomes of corneal transplant surgery and intraocular lens opacification following Descemet's stripping automated endothelial keratoplasty.

PURPOSE: To evaluate the indications for corneal transplantation, the procedures carried out, and the postoperative outcomes and to compare these with previous Irish corneal transplant studies. METHODS: A retrospective review of the case notes of all patients who underwent corneal transplantation under the care of a single surgeon, from 2008 to 2015, was performed. The risk factors for postoperative complications including transplant failure were examined. RESULTS: During the period studied, 42 corneal transplant surgeries were carried out on 40 eyes of 38 patients, 24 of whom were male (63%), median age at surgery was 62 years (range 23-96 years). The most common indication for transplantation was pseudophakic corneal decompensation associated with Fuch's endothelial dystrophy (FED) (n = 13). Seventeen penetrating keratoplasties, 23 lamellar keratoplasties, and two amniotic membrane transplant procedures were carried out. Transplant failure resulting in corneal oedema or repeat corneal transplant surgery (n = 4, 10%), was associated with previous transplant failure in the eye; odds ratio (OR) = 1.58 (p = 0.05), and with comorbid FED, OR = 1.50 (p = 0.02). Intraocular lens opacification occurred in one lens following DSAEK, giving an incidence rate of 7%. CONCLUSIONS: Pseudophakic corneal decompensation is the commonest indication for corneal transplant surgery, with lamellar keratoplasty the most frequent approach in our cohort, reflecting developments observed in corneal transplant surgery elsewhere. Prior corneal transplant failure and Fuch's dystrophy remain important risk factors for failure. The risk of intraocular lens opacification and its potential effects on vision should be elaborated prior to endothelial keratoplasty.

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

STUDY QUESTION: What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? SUMMARY ANSWER: No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). WHAT IS KNOWN ALREADY: Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. STUDY DESIGN, SIZE, DURATION: This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. MAIN RESULTS AND ROLE OF CHANCE: The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A limited number of cases were included. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

Blood metabolite markers of neocortical amyloid-ß burden: discovery and enrichment using candidate proteins.

We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimer's disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimer's Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimer's Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials.

Transforming growth factor-ß1 sustains the survival of Foxp3(+) regulatory cells during late phase of oropharyngeal candidiasis infection.

As CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to T cell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing α-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-ß1 (TGF-ß1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-ß1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-ß1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections.

Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease.

There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.

Ongoing outbreak of Shigella flexneri serotype 3a in men who have sex with men in England and Wales, data from 2009-2011.

Diagnoses of Shigella flexneri in the United Kingdom (UK) are usually travel-related. However, since 2009, there has been an overall increase in UK-acquired cases. The Health Protection Agency has been investigating a national outbreak of S. flexneri detected in 2011 and which is still ongoing. Cases occurred mostly in men who have sex with men and were of serotype 3a. The investigation aimed at obtaining epidemiological data to inform targeted outbreak management and control.

A foodborne outbreak of Salmonella Bareilly in the United Kingdom, 2010.

We report the preliminary findings of the investigation of an outbreak of foodborne Salmonella Bareilly. Between August and November 2010, there were 231 laboratory-confirmed reports of S. Bareilly in the United Kingdom. A case­control study showed that consumption of bean sprouts was significantly associated with illness. The investigation concluded that raising public awareness to ensure the correct preparation of raw bean sprouts during cooking was the principal means of preventing further cases.

Metabolite-biomarker investigations in the life cycle of and infection with Schistosoma.

Schistosome infection is endemic in many Third World countries and affects an estimated 200 million individuals. Over the last few years, a number of investigations have focused on small molecule biomarkers of this infection. These studies were aimed at discovering key molecules relating to the life cycle of the parasite or deciphering metabolic change in the host during infection. In this review these studies are further divided into targeted approaches to find compounds and fingerprinting techniques i.e. metabonomics. A species-specific metabolite or group of biomarkers of the infection have yet to be discovered. For this reason a critical discussion contrasting with established diagnostic methods and future prospects are also provided.

Bidirectional correlation of NMR and capillary electrophoresis fingerprints: a new approach to investigating Schistosoma mansoni infection in a mouse model.

We demonstrate the statistical integration of nuclear magnetic resonance (NMR) spectroscopy and capillary electrophoresis (CE) data in order to describe a pathological state caused by Schistosoma mansoni infection in a mouse model based on urinary metabolite profiles. Urine samples from mice 53 days post infection with S. mansoni and matched controls were analyzed via NMR spectroscopy and CE. The two sets of metabolic profiles were first processed and analyzed independently and were subsequently integrated using statistical correlation methods in order to facilitate cross assignment of metabolites. Using this approach, metabolites such as 3-ureidopropionate, p-cresol glucuronide, phenylacetylglycine, indoxyl sulfate, isocitrate, and trimethylamine were identified as differentiating between infected and control animals. These correlation analyses facilitated structural elucidation using the identification power of one technique to enhance and validate the other, but also highlighted the enhanced ability to detect functional correlations between metabolites, thereby providing potential for achieving deeper mechanistic insight into the biological process.

A national outbreak of verotoxin-producing Escherichia coli O157 associated with consumption of lemon-and-coriander chicken wraps from a supermarket chain.

A national outbreak of verotoxin-producing Escherichia coli O157 infection affected five English regions and Wales. Twelve cases were associated with lemon-and-coriander chicken wrap from a single supermarket chain consumed over a 5-day period. An outbreak investigation aimed to identify the source of infection. Descriptive epidemiology and phenotypic and genotypic tests on human isolates indicated a point-source outbreak; a case-control study showed a very strong association between consumption of lemon-and-coriander chicken wrap from the single supermarket chain and being a case (OR 46.40, 95% CI 5.39-infinity, P=0.0002). Testing of raw ingredients, products and faecal samples from staff in the food production unit did not yield any positive results. The outbreak was probably caused by one contaminated batch of an ingredient in the chicken wrap. Even when current best practice is in place, ready-to-eat foods can still be a risk for widespread infection.

Metabolic fingerprinting with capillary electrophoresis.

Increasingly biomedical studies require a top-down approach that can be achieved by comparing patterns, signatures or "fingerprints" of metabolites that change in response to disease, toxin exposure, environmental or genetic alterations. Capillary electrophoresis is a technique well suited for the analysis of biofluids and extracted tissue. The experimental design requires a multidisciplinary team comprising chemists, informaticians, medics, etc. Here we have reviewed the field of CE fingerprinting and organised the manuscript in four main blocks, Sample treatment is a discussion of the latest methods for extraction of compounds, Analytical methods, deals with the different versions of electrophoretic methods and detection instrumentation, Chemometrics and CE fingerprinting, explains algorithms that have been presented for peak alignment, normalization, data analysis and metabolite identification, and the Applications heading focuses in urine, plasma, organic matter and plant extract studies.

Chromatographic characterisation, under highly aqueous conditions, of a molecularly imprinted polymer binding the herbicide 2,4-dichlorophenoxyacetic acid.

The affinity of a 2,4-dichlorophenoxyacetic acid (2,4-D) molecularly imprinted polymer (MIP), which was synthesised directly in an aqueous organic solvent, for its template (2,4-D) was studied and compared with the affinity exhibited by two other reference (control) polymers, NIPA and NIPB, for the same analyte. Zonal chromatography was performed to establish the optimal selectivity, expressed as imprinting factor (IF), under chromatographic conditions more aqueous than those described so far in the literature. Frontal analysis (FA) was performed on columns packed with these polymers, using an optimized mobile phase composed of methanol/phosphate buffer (50/50, v/v), to extract adsorption isotherm data and retrieve binding parameters from the best isotherm model. Surprisingly, the template had comparable and strong affinity for both MIP (K = 3.8x10(4) M(-1)) and NIPA (K = 1.9x10(4) M(-1)), although there was a marked difference in the saturation capacities of selective and non-selective sites, as one would expect for an imprinted polymer. NIPB acts as a true control polymer in the sense that it has relatively low affinity for the template (K = 8.0x10(2) M(-1)). This work provides the first frontal chromatographic characterization of such a polymer in a water-rich environment over a wide concentration range. The significance of this work stems from the fact that the chromatographic approach used is generic and can be applied readily to other analytes, but also because there is an increasing demand for well-characterised imprinted materials that function effectively in aqueous media and are thus well-suited for analytical science applications involving, for example, biofluids and environmental water samples.

Modelling to assist in wastewater collection system odour and corrosion potential evaluations.

Odour emissions and corrosion concerns can be a constant focus for many wastewater treatment and collection system owners, usually from the first day that their collection systems begin operation. Many sewer systems are reaching the end of their useful life, or have experienced either odour or corrosion issues. This paper shows a link between odour generation and corrosion potential, and how modelling can be used to assist in odour/corrosion assessments of existing wastewater collection systems. A model has been developed that is capable of predicting liquid-phase sulphide generation and subsequent release to overlying sewer headspace as hydrogen sulphide (H2S), where it can be the source of either odour or corrosion problems. This paper presents an overview of the model, and uses a case study involving both odour and corrosion issues to demonstrate the utility in modelling. The model was used to identify potential locations within the system where odour/corrosion may be problematic, as well as assisting in the evaluation of potential odour control alternatives.

Biotechnology-based odour control: design criteria and performance data.

As neighbouring areas continue to encroach upon wastewater treatment plants, there is an increasing need for odour control to mitigate potential negative offsite odorous impacts. One technology that is gaining widespread acceptance is biotechnology, which utilises the inherent ability of certain microorganisms to biodegrade offensive odorous compounds. Two main advantages of this form of treatment over other odour control technologies include the absence of hazardous chemicals and relatively low operation and maintenance requirements. The purpose of this paper is to provide information related to odour control design criteria used in sizing/selecting biotechnology-based odour control technologies, and to provide odour removal performance data obtained from several different biotechnology-based odour control systems. CH2M HILL has collected biotechnology-based odour control performance data over the last several years in order to track the continued performance of various biofilters and biotowers over time. Specifically, odour removal performance data have been collected from soil-, organic- and inorganic-media biofilters and inert inorganic media biotowers. Results indicate that biotechnology-based odour control is a viable and consistent technology capable of achieving high removal performance for odour and hydrogen sulphide. It is anticipated that the information presented in this paper will be of interest to anyone involved with odour control technology evaluation/selection or design review.

Study of short polystyrene monolith-fritted micro-liquid chromatography columns for analysis of neutral and basic compounds.

This study details the effects of poly(styrene-divinylbenzene) (PS-DVB) frits in micro-HPLC columns for the separation of neutral and basic compounds. The procedure comprised the optimization of separations with only monolith or conventional fritted columns followed by method transference to short monolith-fritted columns. It was observed that a superior separation was achieved with the new columns compared to silica-fritted-packed columns once triethylamine (TEA) was added in small percentages. The separation of basic and neutral compounds was achieved in fast analysis times in the isocratic mode.

Opioid switching to improve pain relief and drug tolerability.

BACKGROUND: Patients with cancer, and increasingly chronic non-cancer pain frequently require strong opioids for pain relief. Morphine is the first-line strong opioid of choice for these patients. While most achieve adequate analgesia with morphine, a significant minority either suffer intolerable side-effects, inadequate pain relief, or both. For these patients switching to an alternative opioid is becoming established clinical practice. However, the evidence for the effectiveness of opioid switching does not appear to be established. OBJECTIVES: The aim of this review was to investigate the usefulness of opioid switching for patients with pain. SEARCH STRATEGY: Randomised trials that assessed opioid rotation, switching, or substitution in adults or children with acute or chronic pain were sought through electronic databases and by handsearching relevant journals. Date of the most recent search: January 2003. SELECTION CRITERIA: The search strategy retrieved no randomised controlled trials, and therefore no studies were available to enable a quantitative synthesis that would assess the effectiveness of the strategy of opioid switching. DATA COLLECTION AND ANALYSIS: Given the lack of RCTs, the review examined all case reports, uncontrolled, and retrospective studies in an attempt to determine the current level of evidence. MAIN RESULTS: Fifty-two reports were identified, comprising 23 case reports, 15 retrospective studies/audits and 14 prospective uncontrolled studies. The majority of the reports used morphine as first-line opioid and the most frequently used second-line opioid was methadone. All reports, apart from one, concluded that opioid switching is a useful clinical manoeuvre for improving pain control and/or reducing opioid-related side-effects. REVIEWERS' CONCLUSIONS: For patients with inadequate pain relief and intolerable opioid-related toxicity/adverse effects, a switch to an alternative opioid may be the only option for symptomatic relief. However, the evidence to support the practice of opioid switching is largely anecdotal or based on observational and uncontrolled studies. Randomised trials, including 'N of 1' studies, where a patient acts as their own control, are needed: firstly, to establish the true effectiveness of this clinical practice; secondly, to determine which opioid should be used first-line or second-line; and thirdly, to standardise conversion ratios when switching from one opioid to another.

Latitudinal variation in the prevalence of multiple sclerosis in Ireland, an effect of genetic diversity.

BACKGROUND: Northern Ireland has a high and rising prevalence rate of multiple sclerosis (MS). The most recent survey in 1996 found a rate of 168.7/100 000. Recorded prevalence rates for the south of Ireland, including County Wexford, have been markedly lower and seemed to suggest the existence of a prevalence gradient within the island. OBJECTIVES: To compare the prevalence of multiple sclerosis in Co. Wexford in the south east of Ireland and Co. Donegal in the north west, and to establish whether a variation in prevalence of MS exists within Ireland. METHODS: Patients were referred from multiple sources. Review of clinical case records and/or patient examination confirmed the diagnosis. RESULTS: In Co. Wexford, 126 patients were found to have clinically definite or probable multiple sclerosis with a prevalence rate of 120.7/100 000 (95% confidence intervals (CI) 100.6 to 143.8), which is similar to other areas of similar latitude within the British Isles. In Co. Donegal, 240 people had clinically definite or probable MS with a prevalence rate of 184.6/100 000 (95% CI 162.0 to 209.5). The difference in prevalence rates is statistically significant (Z = 3.94, p = <0.001). CONCLUSION: There is a latitudinal variation in the prevalence rate of MS between the north and the south of Ireland. The increased prevalence of MS seen in Co. Wexford is likely to represent better case ascertainment and improved diagnostic accuracy rather than an actual increase in prevalence. The north/south variation in prevalence may represent a variation in the genetic predisposition to MS between the background populations of the two counties.

Quantification of the sensitivity increase of a micro-high-performance liquid chromatography-electrospray ionization mass spectrometry system with decreasing column diameter.

This study details the sensitivity achieved with capillary columns when used with a micro-HPLC-electrospray ionization MS system. It is comprised of two sections, the first is the comparative study of three columns, one of narrow-bore diameter and two of capillary diameter. The second section compares three columns of decreasing diameter in the capillary scale. All the experiments achieved enhanced sensitivity using capillary columns. The increase in the experimental MS response ranged from -20% to +20% compared to the UV experimental response when decreasing the internal diameter of the columns used. When comparing the experimental MS response to the maximum theoretical UV response achievable, the increase in response ranged from 40 to 50%.