Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

The genetic toolbox for Acidovorax temperans.

Environmental isolates belonging to the genus Acidovorax play a crucial role in degrading a wide range of pollutants. Studies on Acidovorax are currently limited for many species due to the lack of genetic tools. Here, we described the use of the replicon from a small, cryptic plasmid indigenous to Acidovorx temperans strain CB2, to generate stably maintained shuttle vectors. In addition, we have developed a scarless gene knockout technique, as well as establishing green fluorescent protein (GFP) reporter and complementation systems. Taken collectively, these tools will improve genetic manipulations in the genus Acidovorax.

Cost effectiveness of caspofungin vs. voriconazole for empiric therapy in Turkey.

Invasive fungal infections from febrile neutropenia are associated with significant cost and mortality. The mainstay of treatment has been liposomal amphotericin B, however, echinocandins and azoles have shown promise as alternative treatments. Data on clinical efficacy exist, however, data incorporating pharmacoeconomic considerations are required in Turkey. The aim of this study was to investigate the cost effectiveness of caspofungin vs. voriconazole in empiric treatment of febrile neutropenia in Turkey. A decision analytic model was utilised, built upon two randomised-controlled trials and supplemented with expert panel input from clinicians in Turkey. A five-point composite outcome measure was utilised and sensitivity analyses were performed to demonstrate the robustness of the model. The base case scenario resulted in caspofungin being preferred by TL2,533, TL29,256 and TL2,536 per patient treated, successfully treated patient and patient survival, respectively (approx. USD1414, 16 328 and 1415); sensitivity analyses did not change the outcome. Monte Carlo simulation highlighted a 78.8% chance of favouring caspofungin. The result was moderately sensitive to treatment duration and acquisition cost of the antifungal agents compared. This is the first pharmacoeconomic study comparing caspofungin to voriconazole within Turkey, resulting in an advantage towards caspofungin. The study will aid in formulary decision-making based on the clinical and economic consequences of each agent in the Turkish health care setting.

Pharmacoeconomic evaluation of caspofungin versus liposomal amphotericin B in empirical treatment of invasive fungal infections in Turkey.

Invasive fungal infections (IFIs) are a major concern within healthcare systems. This pharmacoeconomic study evaluated the use of caspofungin (CAS) versus liposomal amphotericin B (L-AmB) in the empirical treatment of IFIs within the Turkish healthcare system. A decision-analytic model was adopted, utilising data from a randomised, non-inferiority clinical trial and a panel of clinical experts in Turkey. A five-point composite outcome measure was used to evaluate both agents. Sensitivity analyses were performed. In the base-case scenario, CAS was preferred over L-AmB by Turkish Lira (TL) 3961 per patient treated, TL 12 904 per successfully treated patient and TL 3972 per death averted. One-way sensitivity analysis did not change the study outcome. Monte Carlo simulation concluded a 71.0% chance of the outcome favouring CAS. The results were most sensitive to changes in length of stay. This is the first economic evaluation of the empirical treatment of IFIs in Turkey and suggests that CAS is more cost effective than L-AmB.

Strong selection pressures impact the capacity of flocculating activated sludge bacteria to granulate.

The capacity of activated sludge (AS) microbial populations to form dense granules offers the potential to establish efficiently settleable biomass. This has the potential to circumvent problems around ineffective solids-liquid separation and sensitivity to variable chemical oxygen demand (COD) loads. Although a number of studies have evaluated aerobic laboratory granulation reactors as high-rate treatment systems, the biological processes involved in aerobic granulation are not fully understood. Concomitantly, the impact of operation parameters such as organic loading rates is also important for granulation. The ability of a flocculating AS community to granulate under different selection pressures was evaluated in a laboratory sequencing batch reactor by determining levels of extracellular polymeric substances (EPS) and particle size fractions that developed under feast (4.74 g COD L(-1)) and famine (0.42 g COD L(-1)) nutrient regimes. The efficiency of solid-liquid separation was also measured. Aggregation indices showed levels >94% and a sludge volume index factor of up to 0.94, which strongly suggested granule formation; however, microscopy evaluation showed a mixture of flocs and granules. Particle size analysis revealed binomial distribution patterns of particles in the reactor which shifted to smaller tightly bound particles (<200 µm) although large particles (>600 µm) were also measured during famine conditions. This coincided with increases in EPS levels although EPS quantities were low and it is postulated that this could have impacted granule formation: the EPS in the bacterial aggregates were consumed since the AS community was starved.

Nutrient conditions and reactor configuration influence floc size distribution and settling properties.

Floc formation and settleability is critical for effective solid-liquid separation in many wastewater treatment processes. This study aimed to investigate the relationship between particle size distribution and nutrient conditions in different bioreactor configurations. Size distribution profiles of flocs that formed in continuous (B1), continuous with clarifier and return sludge (B2) and SBR (B3) reactors were investigated in parallel under identical nutrient conditions. An eight-fold dilution of the influent COD of a synthetic dairy processing wastewater resulted in a 'feast and famine' regime that triggered significant effects on the biomass and flocculation characteristics. Floc size analysis of reactor MLSS revealed a shift in floc sizes when reactors were fed with the minimum (famine) COD wastewater feed (0.61 g L(-1)). Increasing floc size distributions were detected for all reactors during the minimum COD feed although different size patterns were observed for different reactor configurations. These increases corresponded with variations in aggregation and EPS quantities. The SBR yielded comparatively larger flocs when operated under both COD feeds as indicated by d(0.9) values (90% of particles ≤ d in size). Overall the results indicated that floc formation and floc size are mediated by nutrient concentrations and represents an important step towards improved solid-liquid separation.

Bilateral rubeosis iridis and rubeotic glaucoma due to peripheral occlusive vasculitis associated with multiple sclerosis.

UNLABELLED: Multiple sclerosis is associated with iridocyclitis, intermediate uveitis, retinal periphlebitis, and optic neuritis. The periphlebitis is known to be rarely sight-threatening as a result of the sequelae of retinal neovascularization. CASE: This is a rare case of bilateral rubeosis iridis and rubeotic glaucoma in the setting of a branch retinal vein occlusion, widespread peripheral periphlebitis, and angiographic peripheral closure associated with "clinically definite" multiple sclerosis. DISCUSSION: The case illustrates the extreme end of the spectrum of peripheral retinal ischemia and neovascularization associated with demyelinating disease, which can present as rubeotic glaucoma. Such patients require a proactive approach to inflammation, neovascularization, and raised intraocular pressure, including systemic immunosuppression, photocoagulation, and augmented trabeculectomy, respectively. As with other causes of peripheral ischemia, a favorable visual outcome can often be achieved using this strategy.

Evaluation of extracellular biopolymer and its impact on bioflocculation in activated sludge bioreactors.

The influence and dynamics of bacterial extracellular polysaccharide (EPS) polymer production and its impact on bioflocculation in activated sludge (AS) bench-scale reactors were investigated. The impact of food to microorganism ratio (F/M), reactor configuration and easily biodegradable carbohydrates in influent streams on biological processes that support or weaken good floc formation and the link with EPS quantity was studied. Bioreactors were run as either sequencing batch or continuous systems using wastewater media with glucose or acetate as C source in different F/M ratios. EPS levels were quantified using mid-infrared spectroscopy which provided a rapid technique for monitoring biological processes within AS WWTP. The analysis revealed an interdependent link between EPS production, sludge settling characteristics and mode of reactor operation. An inverse relationship between F/M ratios and EPS quantities was seen but a positive link between EPS levels and aggregation indices, a measure of the efficiency of inter cell attachment and which indicates good settling properties, was also seen. This indicates that during high F/M conditions in lab-scale AS reactors, low levels of EPS may be produced which could have a negative impact on settling of the biomass. Floc architecture was examined under the microscope. Transient growth of filamentous bacteria was seen in the reactors.

Metastatic cutaneous squamous cell carcinoma of the external ear: a high-risk cutaneous subsite.

INTRODUCTION: Patients with cutaneous squamous cell carcinoma of the external ear may develop metastatic spread to the nearby ipsilateral parotid and/or upper cervical lymph nodes. The literature suggests that the external ear is a high-risk subsite for such tumours, due to nodal metastasis and its associated morbidity and mortality. METHODS: Between 1980 and 2007, 43 patients with a diagnosis of metastatic cutaneous squamous cell carcinoma of the external ear were treated with surgery alone, surgery plus adjuvant radiotherapy, or radiotherapy alone. RESULTS: Patients comprised 39 men and four women. Their median age at diagnosis was 72 years, with a median follow up of 35 months. The median size of the primary lesion was 21 mm, with a median thickness of 7 mm. Fifteen patients presented concurrently with nodal metastases. Thirty patients developed parotid metastases (with positive cervical nodes in six patients), while 13 developed cervical metastases only. Eight patients underwent surgery alone, 32 underwent surgery plus adjuvant radiotherapy, and three received radiotherapy alone. At the last follow up, 15 patients had relapsed and nine had died of their disease, with a median survival after relapse of 5.5 months. CONCLUSION: Patients with metastatic cutaneous squamous cell carcinoma of the external ear have a relatively poor outcome, with a significant number of patients experiencing nodal relapse and death after treatment.

Visualizing CTL activity for different CD8+ effector T cells supports the idea that lower TCR/epitope avidity may be advantageous for target cell killing.

Time-lapse video microscopy allows analysis of the interaction between individual CTLs and adherent peptide-pulsed targets, from contact, to lymphocyte detachment, APC rounding, phosphatidylserine exposure and finally loss of plasma membrane integrity characteristic of end-stage apoptosis. Using in vitro-stimulated effectors specific for the ovalbumin K(b)OVA(257) (OT-I) and influenza A virus D(b)NP(366) and D(b)PA(224) epitopes, no significant correlation was found between the duration of CTL contact and the time to phosphatidylserine exposure or loss of membrane integrity. Furthermore, there were minimal indications that transgenic T cells specific for the K(b)OVA(257) epitope (TCR) diversity had any effect. However, when the analysis was repeated with D(b)NP(366) and D(b)PA(224)-specific CTLs recovered directly from the lungs of mice with influenza pneumonia, the lower avidity D(b)NP(366)-specific set was found to elute much more quickly. Shorter contact time may allow individual CTLs to lyse more targets, suggesting that lower TCR/epitope avidity may be more beneficial than higher epitope avidity for cell-mediated immunity.

Management of the potato cyst nematode (Globodera pallida) with bio-fumigants/stimulants.

Field trials evaluated the effect of four plant-based bio-fumigants/stimulants on population levels of G. pallida and the resulting potato yields and quality. Three formulations contained seaweed biostimulants (Algifol, Nutridip and Metastim) and one bio-fumigant containing mustard and chilli pepper extracts (Dazitol). These were compared with the fumigant nematicide Nemathorin and untreated control plots. The effect of G. pallida on growing potato crops was assessed by recording haulm characteristics which indicated that the nematicide treatment gave most protection. Levels of PCN juveniles and migratory nematodes were assessed during the trial. Plots treated with Nemathorin and Dazitol had fewest PCN, whilst the highest number of migratory nematodes occurred in fallow plots. Sixteen weeks after planting the nematicide treatment produced highest yield and tuber numbers. Dazitol treatment produced a lower yield but the largest tubers.

Management of root knot nematodes in turfgrass using mustard formulations and biostimulants.

The control of nematodes in turfgrass poses particular problems for turf managers. Due to the nature of this specialized "crop" system, many of the options available in agriculture and horticulture are impractical and the range of available chemical controls limited. This is particularly highlighted by the withdrawal of fenamiphos, one of the most widely used nematicides in the turfgrass industry. Mustard products are known to release allyl isothiocyanate, a potent nematicide. Laboratory based trials have shown mustard formulations can release enough of this chemical to significantly reduce numbers of root knot nematodes in pot trials using sand based soils. During 2005, trialling at a number of golf courses assessed the efficacy of mustard as a practical alternative to fenamiphos. During heavy nematode infestations, turf grass is exposed to high levels of stress resulting from direct nematode feeding damage as well as the usual environmental stresses imposed by low cutting and heavy wear and tear during play. Stress relief using biostimulants has proven useful in helping maintaining turf cover in these situations and can be applied as part of the normal turf management programme.

The virus-immunity ecosystem.

The ecology of pathogenic viruses can be considered both in the context of survival in the macro-environments of nature, the theme pursued generally by epidemiologists, and in the micro-environments of the infected host. The long-lived, complex, higher vertebrates have evolved specialized, adaptive immune systems designed to minimise the consequences of such parasitism. Through evolutionary time, the differential selective pressures exerted variously by the need for virus and host survival have shaped both the "one-host" viruses and vertebrate immunity. With the development of vaccines to protect us from many of our most familiar parasites, the most dangerous pathogens threatening us now tend to be those "emerging", or adventitious, infectious agents that sporadically enter human populations from avian or other wild-life reservoirs. Such incursions must, of course, have been happening through the millenia, and are likely to have led to the extraordinary diversity of recognition molecules, the breadth in effector functions, and the persistent memory that distinguishes the vertebrate, adaptive immune system from the innate response mechanisms that operate more widely through animal biology. Both are important to contemporary humans and, particularly in the period immediately following infection, we still rely heavily on an immediate response capacity, elements of which are shared with much simpler, and more primitive organisms. Perhaps we will now move forward to develop useful therapies that exploit, or mimic, such responses. At this stage, however, most of our hopes for minimizing the threat posed by viruses still focus on the manipulation of the more precisely targeted, adaptive immune system.

Ontogenetic development of the gastrointestinal microbiota in the marine herbivorous fish Kyphosus sydneyanus.

Molecular techniques were used to investigate the composition and ontogenetic development of the intestinal bacterial community in the marine herbivorous fish Kyphosus sydneyanus from the north eastern coast of New Zealand. Previous work showed that K. sydneyanus maintains an exclusively algivorous diet throughout post-settlement life and passes through an ontogenetic diet shift from a juvenile diet which is readily digestible to an adult diet high in refractory algal metabolites. Terminal restriction fragment length polymorphism (T-RFLP) analysis was used to investigate the relationship between bacterial community structure and fish size. Bacterial diversity was higher in posterior gut sections than anterior gut sections, and in larger fish than in smaller fish. Partial sequencing of bacterial 16S rDNA genes PCR amplified and cloned from intestine content samples was used to identify the phylogenetic affiliation of dominant gastrointestinal bacteria. Phylogenetic analysis of clones showed that most formed a clade within the genus Clostridium, with one clone associated with the parasitic mycoplasmas. No bacteria were specific to a particular intestinal section or size class of host, though some appeared more dominant than others and were established in smaller fishes. Clones closely related to C. lituseburense were particularly dominant in most intestine content samples. All bacteria identified in the intestinal samples were phylogenetically related to those possessing fermentative type metabolism. Short-chain fatty acids in intestinal fluid samples increased from 15.6 +/- 2.1 mM in fish <100 mm to 51.6 +/- 5.5 mM in fish >300 mm. The findings of this study support the hypothesis that the ontogenetic diet shift of K. sydneyanus is accompanied by an increase in the diversity of intestinal microbial symbionts capable of degrading refractory algal metabolites into short-chain fatty acids, which can then be assimilated by the host.