The Berkeley Contact Lens Extended Wear Study. Part I : Study design and conduct.

ObjectiveThe primary aim of the Berkeley Contact Lens Extended Wear Study (CLEWS) was to test the hypotheses that extended wear of rigid gas-permeable (RGP) contact lenses with greater oxygen permeability (Dk) reduces the incidence of contact lens-associated keratopathy (CLAK) and increases the survival rate in RGP extended wear (EW). In this article we describe the clinical trial design in detail, present the results of subject recruitment and retention, and provide the baseline demographic and ocular characteristics of the CLEWS subjects, whose data will be analyzed to address the study aims in a companion article.DesignA randomized, concurrently controlled clinical trial.InterventionSubjects were fitted with day wear (DW) high-Dk RGP lenses and then adapted to EW. Subjects who adapted to EW were then randomly assigned to either high- or medium-Dk RGP lenses for 12 months of 6-nights/week EW.Main outcome measuresSlit-lamp assessment and grading of 17 possible keratopathies, measurement of refractive error and corneal curvature, and symptoms. Follow-up data were collected every 3 months.ResultsFrom 545 subjects entering the DW adaptation phase, 201 adapted to EW and were randomly assigned to medium- or high-Dk lenses for 12 months of EW. The baseline characteristics of the two study groups were similar and did not differ from the 344 DW subjects who failed to adapt to EW. The distributions of oxygen transmissibility for the two study groups were disjoint, indicating that each group received distinctly different levels of hypoxia.ConclusionsWe show that CLEWS was appropriately designed to address the study hypotheses, was conducted with regard for the safety of the subjects, and adhered to rigorous protocols designed to control for bias and ensure the integrity of study data. We establish the internal validity of between-group statistical comparisons and characterize our study population to permit informed evaluation of the applicability of our results to the contact lens-wearing population in general

The Berkeley Contact Lens Extended Wear Study. Part II : Clinical results.

ObjectiveTo describe the principal clinical outcomes associated with 12 months use of rigid gas-permeable (RGP) extended wear contact lenses and address two primary study questions: (1) does extended wear (EW) of high oxygen transmissibility (Dk/t) RGP lenses reduce the incidence of ocular complications, and (2) does the wearing of high-Dk/t lenses reduce the rate of failure to maintain 6-night RGPEW over 12 months?DesignA randomized, concurrently controlled clinical trial.InterventionSubjects who adapted to EW with high Dk (oxygen permeability) RGP lenses were randomized to either high Dk or medium-Dk RGP lenses for 12 months of 6-night EW.Main outcome measuresContact lens-associated keratopathies (CLAK), changes in refractive error and corneal curvature, and survival in EW.ResultsTwo hundred one subjects were randomized to medium or high-Dk lenses for 12 months of EW. Sixty-two percent of the subjects in each group completed 12 months of EW; however, the probability of failure was significantly greater for the medium-Dk group. Although the risk of complications was similar for the two groups, the number of CLAK events that led to termination were 16 versus 5 for the medium-Dk and high-Dk groups, respectively. This suggests that the type of adverse response or the inability to reverse an adverse event was different for the group being exposed to the lower oxygen dose.ConclusionsThe level of oxygen available to the cornea has a significant impact on maintaining successful RGP extended contact lens wear, but not on the initial onset of CLAK. The number of clinical events leading to termination was substantially higher for the medium Dk group, which suggests that corneal hypoxia is an important factor in the development of CLAK. Although overnight contact lens wear should be recommended with caution and carefully monitored for early detection of ocular complications, it appears that high-Dk RGP lenses can be a safe and effective treatment for correction of refractive error for most individuals who can adapt to EW

Sectoral specialisation in the EU a macroeconomic perspective

This paper analyses trends in sectoral specialisation in the EU and concludes the following: 1) The European production structure appears more homogenous than that of the US. 2) While sectoral specialisation has shown a slight increase in some smaller euro area countries towards the end-1990s, it is too early to detect any potential impact of EMU. 3) Despite some changes in sectoral composition, the business cycles of euro area countries became more synchronised over the 1990s, which may be seen as reassuring from the point of view of the single monetary policy. 4) Sectoral re-allocation accounts for as much as 50% of the increase in labour productivity growth in business sector services in the euro area. 5) The slowdown of European labour productivity growth relative to the US since the mid-1990s is explained by a stronger performance in the US wholesale and retail trade, financial intermediation and high-tech manufacturing sectors.

The Nature of Working Memory for Braille

Blind individuals have been shown on multiple occasions to compensate for their loss of sight by developing exceptional abilities in their remaining senses. While most research has been focused on perceptual abilities per se in the auditory and tactile modalities, recent work has also investigated higher-order processes involving memory and language functions. Here we examined tactile working memory for Braille in two groups of visually challenged individuals (completely blind subjects, CBS; blind with residual vision, BRV). In a first experimental procedure both groups were given a Braille tactile memory span task with and without articulatory suppression, while the BRV and a sighted group performed a visual version of the task. It was shown that the Braille tactile working memory (BrWM) of CBS individuals under articulatory suppression is as efficient as that of sighted individuals' visual working memory in the same condition. Moreover, the results suggest that BrWM may be more robust in the CBS than in the BRV subjects, thus pointing to the potential role of visual experience in shaping tactile working memory. A second experiment designed to assess the nature (spatial vs. verbal) of this working memory was then carried out with two new CBS and BRV groups having to perform the Braille task concurrently with a mental arithmetic task or a mental displacement of blocks task. We show that the disruption of memory was greatest when concurrently carrying out the mental displacement of blocks, indicating that the Braille tactile subsystem of working memory is likely spatial in nature in CBS. The results also point to the multimodal nature of working memory and show how experience can shape the development of its subcomponents

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base

Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination.

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000-11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved 'horizontal ice core' from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600-12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Lectin-like bacteriocins from pseudomonas spp. utilise D-rhamnose containing lipopolysaccharide as a cellular receptor

Lectin-like bacteriocins consist of tandem monocot mannose-binding domains and display a genus-specific killing activity. Here we show that pyocin L1, a novel member of this family from Pseudomonas aeruginosa, targets susceptible strains of this species through recognition of the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide that is predominantly a homopolymer of d-rhamnose. Structural and biophysical analyses show that recognition of CPA occurs through the C-terminal carbohydrate-binding domain of pyocin L1 and that this interaction is a prerequisite for bactericidal activity. Further to this, we show that the previously described lectin-like bacteriocin putidacin L1 shows a similar carbohydrate-binding specificity, indicating that oligosaccharides containing d-rhamnose and not d-mannose, as was previously thought, are the physiologically relevant ligands for this group of bacteriocins. The widespread inclusion of d-rhamnose in the lipopolysaccharide of members of the genus Pseudomonas explains the unusual genus-specific activity of the lectin-like bacteriocins

Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs

Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention