Diagnosing Optic Disc Drusen in the Modern Imaging Era: A Practical Approach.

Optic disc drusen (ODD) are a well-recognised cause of an elevated optic disc appearance. When visible with ophthalmoscopy and fundus photography, ODD are readily identified. Yet, in more subtle cases of ODD, ancillary testing may be needed to render the diagnosis. Facilitating the diagnosis of ODD has clinical relevance, because affected individuals may otherwise undergo unnecessary costly and invasive investigations to rule out raised intracranial pressure and other causes of optic disc oedema. In this review, the role of established and emerging optical coherence tomography (OCT) techniques in the diagnosis and management of ODD cases is reviewed. A practical approach is taken to explain how to optimise use of commercially available OCT technology in the clinical setting. Optical coherence tomography provides many advantages over other imaging modalities in the diagnosis of ODD, including the ability to correlate retinal measures of neuroaxonal structure with drusen characteristics. Earlier spectral domain OCT techniques, however, were hindered by poor penetrance. In the modern imaging era, enhanced depth imaging OCT and swept source OCT enable higher resolution of ODD and other optic nerve head structures that might otherwise be mistaken for drusen. Ongoing studies featuring OCT angiography indicate that this technique may provide complementary information about microvascular supply that correlate with structural measures of optic nerve injury. Advances in OCT will continue to improve diagnostic accuracy and inform clinical understanding regarding structure-function correlations germane to the longitudinal follow up of ODD patients.

Randomized clinical trial of endovenous laser ablation versus direct and indirect radiofrequency ablation for the treatment of great saphenous varicose veins.

BACKGROUND: The current treatment strategy for many patients with varicose veins is endovenous thermal ablation. The most common forms of this are endovenous laser ablation (EVLA) and radiofrequency ablation (RFA). However, at present there is no clear consensus on which of these treatments is superior. The objective of this study was to compare EVLA with two forms of RFA: direct RFA (dRFA; radiofrequency-induced thermotherapy) and indirect RFA (iRFA; VNUS ClosureFast™). METHODS: Patients with symptomatic great saphenous vein (GSV) incompetence were randomized to receive EVLA, dRFA or iRFA. Patients were followed up at 2 weeks, 6 and 12 months. The primary outcome was GSV occlusion rate. Secondary outcomes included Venous Clinical Severity Score (VCSS), Aberdeen Varicose Vein Questionnaire (AVVQ) score and adverse events. RESULTS: Some 450 patients received the allocated treatment (EVLA, 148; dRFA, 152; iRFA, 150). The intention-to-treat analysis showed occlusion rates of 75·0 (95 per cent c.i. 68·0 to 82·0), 59·9 (52·1 to 67·7) and 81·3 (75·1 to 87·6) per cent respectively after 1 year (P = 0·007 for EVLA versus dRFA, P < 0·001 for dRFA versus iRFA, P = 0·208 for EVLA versus iRFA). VCSS improved significantly for all treatments with no significant differences between them. AVVQ scores also improved significantly for all treatments, but iRFA had significantly better scores than dRFA at 12 months. Significantly more adverse events were reported after treatment with EVLA (103) than after dRFA (61) and iRFA (65), especially more pain. CONCLUSION: Primary GSV occlusion rates were better after iRFA and EVLA than dRFA. All three interventions were effective in improving the clinical severity of varicose veins at 1 year.

Evolution from Ferromagnetism to Antiferromagnetism in Yb(Rh_{1-x}Co_{x})_{2}Si_{2}.

Yb(Rh_{1-x}Co_{x})_{2}Si_{2} is a model system to address two challenging problems in the field of strongly correlated electron systems. The first is the intriguing competition between ferromagnetic (FM) and antiferromagnetic (AFM) order when approaching a magnetic quantum critical point (QCP). The second is the occurrence of magnetic order along a very hard crystalline electric field (CEF) direction, i.e., along the one with the smallest available magnetic moment. Here, we present a detailed study of the evolution of the magnetic order in this system from a FM state with moments along the very hard c direction at x=0.27 towards the yet unknown magnetic state at x=0. We first observe a transition towards an AFM canted state with decreasing x and then to a pure AFM state. This confirms that the QCP in YbRh_{2}Si_{2} is AFM, but the phase diagram is very similar to those observed in some inherently FM systems like NbFe_{2} and CeRuPO, which suggests that the basic underlying instability might be FM. Despite the huge CEF anisotropy the ordered moment retains a component along the c axis also in the AFM state. The huge CEF anisotropy in Yb(Rh_{1-x}Co_{x})_{2}Si_{2} excludes that this hard-axis ordering originates from a competing exchange anisotropy as often proposed for other heavy-fermion systems. Instead, it points to an order-by-disorder based mechanism.

Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial.

BACKGROUND: Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD) refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking. OBJECTIVES: To investigate long-term effectiveness, safety and drug survival of MTX and AZA. METHODS: In an open-label follow-up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves. RESULTS: Thirty-five of 43 originally included patients participated, of whom 27 completed the follow-up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1). CONCLUSIONS: Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD.

Cascade of Magnetic-Field-Induced Lifshitz Transitions in the Ferromagnetic Kondo Lattice Material YbNi_{4}P_{2}.

A ferromagnetic quantum critical point is thought not to exist in two- and three-dimensional metallic systems yet is realized in the Kondo lattice compound YbNi_{4}(P,As)_{2}, possibly due to its one-dimensionality. It is crucial to investigate the dimensionality of the Fermi surface of YbNi_{4}P_{2} experimentally, but common probes such as angle-resolved photoemission spectroscopy and quantum oscillation measurements are lacking. Here, we study the magnetic-field dependence of transport and thermodynamic properties of YbNi_{4}P_{2}. The Kondo effect is continuously suppressed, and additionally we identify nine Lifshitz transitions between 0.4 and 18 T. We analyze the transport coefficients in detail and identify the type of Lifshitz transitions as neck or void type to gain information on the Fermi surface of YbNi_{4}P_{2}. The large number of Lifshitz transitions observed within this small energy window is unprecedented and results from the particular flat renormalized band structure with strong 4f-electron character shaped by the Kondo lattice effect.

Exploring the methods of data analysis in multifocal visual evoked potentials.

PURPOSE: The multifocal visual evoked potential (mfVEP) provides a topographical assessment of visual function, which has already shown potential for use in patients with glaucoma and multiple sclerosis. However, the variability in mfVEP measurements has limited its broader application. The purpose of this study was to compare several methods of data analysis to decrease mfVEP variability. METHODS: Twenty-three normal subjects underwent mfVEP testing. Monocular and interocular asymmetry data were analyzed. Coefficients of variability in amplitude were examined using peak-to-peak, root mean square (RMS), signal-to-noise ratio (SNR) and logSNR techniques. Coefficients of variability in latency were examined using second peak and cross-correlation methods. RESULTS: LogSNR and peak-to-peak methods had significantly lower intra-subject variability when compared with RMS and SNR methods. LogSNR had the lowest inter-subject amplitude variability when compared with peak-to-peak, RMS and SNR. Average latency asymmetry values for the cross-correlation analysis were 1.7 ms (CI 95 % 1.2-2.3 ms) and for the second peak analysis 2.5 ms (CI 95 % 1.7-3.3 ms). A significant difference was found between cross-correlation and second peak analysis for both intra-subject variability (p < 0.001) and inter-subject variability (p < 0.001). CONCLUSIONS: For a comparison of amplitude data between groups of patients, the logSNR or SNR methods are preferred because of the smaller inter-subject variability. LogSNR or peak-to-peak methods have lower intra-subject variability, so are recommended for comparing an individual mfVEP to previous published normative data. This study establishes that the choice of mfVEP data analysis method can be used to decrease variability of the mfVEP results.

Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen.

A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH4, C2H2, HCN, and NH3). With the help of OES, the rotational temperature of the screen plasma could be determined.

The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study.

BACKGROUND AND PURPOSE: Our aim was to prospectively describe the course of headache during the first year of idiopathic intracranial hypertension (IIH). METHODS: Patients with newly diagnosed IIH were consecutively included from December 2010 to June 2013. Treatment according to standard guidelines was initiated. Headache history was obtained by headache diaries and standardized interviews performed at baseline and after 1, 2, 3 and 12 months. Parallel changes in papilledema were assessed by optical coherence tomography (OCT). All patients had comprehensive neuro-ophthalmological examinations including automated perimetry. RESULTS: Forty-four patients were included. Thirty-five patients completed the 12-month follow-up. Dramatic improvement in headache occurred within the first weeks after diagnosis. After 1 year, 15 patients reported no or only infrequent headache. However, 15 of the remaining 20 patients reported sustained chronic headache. Early age of onset and high diagnostic intracranial pressure (ICP) were associated with better headache outcome (≤1 headache days/month) after a year. Papilledema decreased rapidly within the first 2 months of diagnosis. After 1 year, OCT measures had normalized. Visual outcome was excellent in most patients. CONCLUSIONS: Although headache in 43% of patients responded well to ICP management, sustained long-term headache was seen in the remaining patients, despite resolution of papilledema. Headache in IIH may thus be attributed to more complex mechanisms than ICP elevation alone. High ICP and young age were associated with better headache outcome. Early treatment according to standard guidelines seems sufficient to ensure excellent visual outcome in the vast majority of patients.

Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord.

Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective-like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.

Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study.

BACKGROUND: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). PATIENTS AND METHODS: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily. RESULTS: The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days). CONCLUSION: Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

High-throughput characterization of stresses in thin film materials libraries using Si cantilever array wafers and digital holographic microscopy.

We report the development of an advanced high-throughput stress characterization method for thin film materials libraries sputter-deposited on micro-machined cantilever arrays consisting of around 1500 cantilevers on 4-inch silicon-on-insulator wafers. A low-cost custom-designed digital holographic microscope (DHM) is employed to simultaneously monitor the thin film thickness, the surface topography and the curvature of each of the cantilevers before and after deposition. The variation in stress state across the thin film materials library is then calculated by Stoney's equation based on the obtained radii of curvature of the cantilevers and film thicknesses. DHM with nanometer-scale out-of-plane resolution allows stress measurements in a wide range, at least from several MPa to several GPa. By using an automatic x-y translation stage, the local stresses within a 4-inch materials library are mapped with high accuracy within 10 min. The speed of measurement is greatly improved compared with the prior laser scanning approach that needs more than an hour of measuring time. A high-throughput stress measurement of an as-deposited Fe-Pd-W materials library was evaluated for demonstration. The fast characterization method is expected to accelerate the development of (functional) thin films, e.g., (magnetic) shape memory materials, whose functionality is greatly stress dependent.

Malaysian and Thai smokers' beliefs about the harmfulness of 'light' and menthol cigarettes.

OBJECTIVE: This study explored the extent to which Malaysian and Thai smokers believe "light" and menthol cigarettes are less harmful than "regular" cigarettes and the correlates of these beliefs. METHODS: The study used data from wave 1 of the International Tobacco Control Southeast Asia Survey. 2006 adult smokers (95.3% male) from Malaysia and 2000 adult smokers (94.5% male) from Thailand were interviewed face to face in 2005. RESULTS: 29% of Malaysian respondents reported currently smoking light cigarettes and 14% menthols, with 19% agreeing that lights are less harmful and 16% agreeing that menthols are less harmful. 38% of Thai respondents reported currently smoking light cigarettes and 19% menthols, with 46% agreeing that lights are less harmful and 35% agreeing that menthols are less harmful. Malaysian smokers reporting current use of light or menthol cigarettes were more likely to believe that they are less harmful. Reported use of lights did not relate to beliefs for Thai respondents. The belief that light and/or menthol cigarettes are less harmful was strongly related to the belief that they have smoother smoke. CONCLUSIONS: The experience of smoother smoke is likely to produce some level of belief in reduced harm, regardless of how brands are labelled and whether or not Federal Trade Commission FTC/International Organisation for Standardisation tar, nicotine and carbon monoxide yield figures are used.

A645G (Lys216Glu) polymorphism of the bactericidal/permeability-increasing protein gene in periodontal disease.

Bactericidal/permeability-increasing protein (BPI) is a member of the pattern recognition receptors of the innate immune system and recognizes lipopolysaccharides (LPS), a bacterial component belonging to the pathogen-associated molecular patterns (PAMPs). BPI mediates the neutralization of LPS and increases the phagocytosis and cytotoxicity against bacteria. Recently, the functionally effective polymorphism A645G resulting in the amino acid alteration Lys216Glu has been described. The aim of the study was to investigate the association of the A645G polymorphism with chronic periodontal disease. The study population comprised 123 patients with periodontal disease (36 with mild, 52 with moderate and 35 with severe periodontitis) and 122 healthy, unrelated control individuals. Genotyping of the BPI gene polymorphism A645G (Lys216Glu) was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. Statistical analysis was carried out employing the chi(2) test with Yates correction. Genotype and allele frequencies of the polymorphism tested herein showed no significant differences between periodontal disease as compared to the control group. The frequencies of the G allele were 52.4% in patients with periodontal disease and 49.2% in the control individuals (P = 0.528). Moreover, no significant associations could be detected after stratification for disease severity and according to gender. The present study does not give evidence for the contribution of the BPI gene to the genetic background of chronic periodontal disease.

Water transport in the brain: role of cotransporters.

It is generally accepted that cotransporters transport water in addition to their normal substrates, although the precise mechanism is debated; both active and passive modes of transport have been suggested. The magnitude of the water flux mediated by cotransporters may well be significant: both the number of cotransporters per cell and the unit water permeability are high. For example, the Na(+)-glutamate cotransporter (EAAT1) has a unit water permeability one tenth of that of aquaporin (AQP) 1. Cotransporters are widely distributed in the brain and participate in several vital functions: inorganic ions are transported by K(+)-Cl(-) and Na(+)-K(+)-Cl(-) cotransporters, neurotransmitters are reabsorbed from the synaptic cleft by Na(+)-dependent cotransporters located on glial cells and neurons, and metabolites such as lactate are removed from the extracellular space by means of H(+)-lactate cotransporters. We have previously determined water transport capacities for these cotransporters in model systems (Xenopus oocytes, cell cultures, and in vitro preparations), and will discuss their role in water homeostasis of the astroglial cell under both normo- and pathophysiologal situations. Astroglia is a polarized cell with EAAT localized at the end facing the neuropil while the end abutting the circulation is rich in AQP4. The water transport properties of EAAT suggest a new model for volume homeostasis of the extracellular space during neural activity.

Hepatic gene expression patterns in thyroid hormone-treated hypothyroid rats.

Thyroid hormone (T3) is essential for normal development, differentiation and metabolic balance. We have performed DNA microarray experiments using hepatic RNA from hypothyroid and T3-treated hypothyroid rats in order to characterize T3-induced gene expression patterns after various time points (6, 24 and 48 h after the administration of the hormone). Sixty-two of 4608 different genes displayed a reproducible T3-response, and cluster analysis divided these differentially regulated genes into six expression patterns. Thirty-six genes were not significantly regulated within the first 24 h. Transient transfection experiments of eight late-induced gene promoters failed to detect a thyroid hormone response element within their regulatory elements, suggesting an indirect activation mechanism(s). In search for an intermediate factor of T3 action, we examined whether various rather ubiquitous transcription factors, peroxisome proliferator-activated receptors (PPARs) and coactivators of the PPARgamma coactivator 1 family (PGC-1) are regulated by T3. Only PPARgamma and PERC/PGC-1beta exhibit a significant T3-response within the first 6 h after treatment, identifying these factors as candidate components for mediating the late-induced expression pattern. Regulation of early-induced genes within the first 6 h after administration of T3 on transcript levels correlates with altered protein levels after 24 and 48 h in vivo.

Multiplex detection of hotspot mutations by rolling circle-enabled universal microarrays.

Detection of somatic low abundance mutations in early cancer development requires a discriminatory, specific, and high-throughput methodology. In this study we report specific, discriminatory detection of low abundance mutations through a novel combination of rolling circle amplification (Nat Genet 1998; 19:225-232) and PCR ligation detection reaction on a universal oligonucleotide microarray (J Mol Biol 1999; 292:251-262). After mutation-specific multiplex ligation and hybridization of 17 pairs of probes to a generic microarray, the ligated probes were visualized. The multiplex mutation-specific ligation is possible only because rolling circle amplification permits quantification of previously undetectable hybridization events conducive to the detection of a single mutation from within a pool of over 100 wild-type alleles. This system is readily adaptable to high-throughput automation using a robot such as the Biomek platform.

Cognitive and neural mechanisms of emotional memory.

A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory for emotional stimuli. Recent findings from neuroimaging, neuropsychological, drug and neural stimulation studies indicate that emotional stimuli engage specific cognitive and neural mechanisms that enhance explicit memory. Emotional arousal influences memory via factors that act during memory encoding (attention and elaboration) and factors that modulate memory consolidation. Across studies, the amygdala has been consistently implicated as playing a key role in enhancing explicit memory for both pleasant and unpleasant emotional stimuli through modulation of encoding and consolidation processes.