Exchange Rate Dynamics and Central Bank Interventions: On the (De)Stabilizing Nature of Targeting Long-Run Fundamentals Interventions.

We develop a foreign exchange market model in which a market maker adjusts the exchange rate with respect to the trading behavior of chartists, fundamentalists and a central bank. While chartists bet on the persistence of bull and bear markets, fundamentalists speculate on mean reversion. The central bank seeks to stabilize the foreign exchange market by placing buy (sell) orders when the undervaluation (overvaluation) of the exchange rate exceeds a certain threshold. Since a one-dimensional piecewise-linear discontinuous map with three branches determines the evolution of the exchange rate, we use a combination of analytical and numerical tools to explore the extent to which the central bank is able to tame the behavior of the foreign exchange market.

Automated detection and segmentation of intracranial hemorrhage suspect hyperdensities in non-contrast-enhanced CT scans of acute stroke patients.

OBJECTIVES: Artif icial intelligence (AI)-based image analysis is increasingly applied in the acute stroke field. Its implementation for the detection and quantification of hemorrhage suspect hyperdensities in non-contrast-enhanced head CT (NCCT) scans may facilitate clinical decision-making and accelerate stroke management. METHODS: NCCTs of 160 patients with suspected acute stroke were analyzed regarding the presence or absence of acute intracranial hemorrhages (ICH) using a novel AI-based algorithm. Read was performed by two blinded neuroradiology residents (R1 and R2). Ground truth was established by an expert neuroradiologist. Specificity, sensitivity, and area under the curve were calculated for ICH and intraparenchymal hemorrhage (IPH) detection. IPH-volumes were segmented and quantified automatically by the algorithm and semi-automatically. Intraclass correlation coefficient (ICC) and Dice coefficient (DC) were calculated. RESULTS: In total, 79 of 160 patients showed acute ICH, while 47 had IPH. Sensitivity and specificity for ICH detection were 0.91 and 0.89 for the algorithm; 0.99 and 0.98 for R1; and 1.00 and 0.98 for R2. Sensitivity and specificity for IPH detection were 0.98 and 0.89 for the algorithm; 0.83 and 0.99 for R1; and 0.91 and 0.99 for R2. Interreader reliability for ICH and IPH detection showed strong agreements for the algorithm (0.80 and 0.84), R1 (0.96 and 0.84), and R2 (0.98 and 0.92), respectively. ICC indicated an excellent (0.98) agreement between the algorithm and the reference standard of the IPH-volumes. The mean DC was 0.82. CONCLUSION: The AI-based algorithm reliably assessed the presence or absence of acute ICHs in this dataset and quantified IPH volumes precisely. KEY POINTS: • Artificial intelligence (AI) is able to detect hyperdense volumes on brain CTs reliably. • Sensitivity and specificity are highest for the detection of intraparenchymal hemorrhages. • Interreader reliability for hemorrhage detection shows strong agreement for AI and human readers.

Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer.

BACKGROUND: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or ≥2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30 mg/m2 and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). CONCLUSIONS: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. REGISTERED CLINICAL TRIAL NUMBER: NCT00798655.

Immune biomarkers of anti-EGFR monoclonal antibody therapy.

The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.

Attenuation of treatment effect due to measurement variability in assessment of progression-free survival.

For normally distributed data analyzed with linear models, it is well known that measurement error on an independent variable leads to attenuation of the effect of the independent variable on the dependent variable. However, for time-to-event variables such as progression-free survival (PFS), the effect of the measurement variability in the underlying measurements defining the event is less well understood. We conducted a simulation study to evaluate the impact of measurement variability in tumor assessment on the treatment effect hazard ratio for PFS and on the median PFS time, for different tumor assessment frequencies. Our results show that scan measurement variability can cause attenuation of the treatment effect (i.e. the hazard ratio is closer to one) and that the extent of attenuation may be increased with more frequent scan assessments. This attenuation leads to inflation of the type II error. Therefore, scan measurement variability should be minimized as far as possible in order to reveal a treatment effect that is closest to the truth. In disease settings where the measurement variability is shown to be large, consideration may be given to inflating the sample size of the study to maintain statistical power.

Material-Specific Roadmap Modes Can Improve the Visibility of Liquid Embolic Agents for Endovascular Embolization: A Systematic In Vitro Study.

BACKGROUND AND PURPOSE: Endovascular embolization using liquid embolic agents is a safe and effective treatment option for AVMs and fistulas. Because reliable visibility of these liquid embolic agents is essential for intraprocedural visual control to prevent complications, novel angiographic systems are equipped with material-specific roadmap modes. The aim of this study was the systematic in vitro comparison of conventional and material-specific roadmap modes regarding the visibility of the most used liquid embolic agents. MATERIALS AND METHODS: A recently introduced in vitro model, resembling cerebral vessels, was embolized with Onyx 18, Squid 18, PHIL 25%, and n-BCA mixed with iodized oil (n = 4 for each liquid embolic agent), as well as with contrast medium and saline, both serving as a reference. Imaging was performed in conventional and material-specific roadmap modes. The visibility of the liquid embolic agents in both modes was compared quantitatively and qualitatively. RESULTS: Significant differences between conventional and material-specific roadmap modes regarding the visibility of the liquid embolic agents were observed for all study groups. All liquid embolic agents were better visible in the material-specific roadmap modes compared with the conventional mode in qualitative and quantitative analyses (eg, Onyx in conventional-versus-material-specific modes along the 1.0-mm sector: mean contrast-to-noise ratio, 5.69 [SD, 0.85] versus 47.18 [SD, 5.72]; P < .001, respectively). CONCLUSIONS: In this in vitro study, we demonstrated a better visibility of all investigated liquid embolic agents by using material-specific roadmap modes compared with the conventional roadmap technique. Especially in complex anatomic situations, these novel roadmap modes could improve the visual control and thus the safety and efficacy of embolization procedures in clinical practice.

Imaging Artifacts of Liquid Embolic Agents on Conventional CT in an Experimental in Vitro Model.

BACKGROUND AND PURPOSE: Endovascular embolization using liquid embolic agents is a safe and effective treatment option for AVMs and dural arteriovenous fistulas. The aim of this study was to assess the degree of artifact inducement by the most frequently used liquid embolic agents in conventional CT in an experimental in vitro model. MATERIALS AND METHODS: Dimethyl-sulfoxide-compatible tubes were filled with the following liquid embolic agents (n = 10, respectively): Onyx 18, all variants of Squid, PHIL 25%, PHIL LV, and n-BCA mixed with iodized oil. After inserting the tubes into a CT imaging phantom, we acquired images. Artifacts were graded quantitatively by the use of Hounsfield units in a donut-shaped ROI using a customized software application that was specifically designed for this study and were graded qualitatively using a 5-point scale. RESULTS: Quantitative and qualitative analyses revealed the most artifacts for Onyx 18 and the least artifacts for n-BCA, PHIL 25%, and PHIL LV. Squid caused more artifacts compared with PHIL, both for the low-viscosity and for the extra-low-viscosity versions (eg, quantitative analysis, Squid 18: mean ± SD, 30.3 ± 9.7 HU versus PHIL 25%: mean ± SD, 10.6 ± 0.8 HU; P < .001). Differences between the standard and low-density variants of Squid were observed only quantitatively for Squid 12. There were no statistical differences between the different concentrations of Squid and PHIL. CONCLUSIONS: In this systematic in vitro analysis investigating the most commonly used liquid embolic agents, relevant differences in CT imaging artifacts could be demonstrated. Ethylene-vinyl alcohol-based liquid embolic agents induced more artifacts compared with liquid embolic agents that use iodine as a radiopaque component.

[Significance of atopic dermatitis in outpatient medical care. Analysis of health care data from Saxony]. / Bedeutung des atopischen Ekzems in der ambulanten medizinischen Versorgung. Eine Sekundärdatenanalyse.

BACKGROUND: Data on health services utilization by children and adults due to atopic eczema (AE) are scarce, as well as data concerning the epidemiology of AE in adults. METHODS: Utilizing a population-based administrative health care database from Saxony, Germany, that covers comprehensive information on outpatient health care of 2.1 million individuals in 2003 and 2004, this study describes the relevance of AE as the proportion of children and adults with outpatient visits due to AE (ICD10 L20). Age- and sex-stratified prevalences of AE were estimated as the proportion of individuals insured by the Saxony Compulsory Health Insurance (AOK Sachsen), who were diagnosed as having AE at least twice within the study period. RESULTS: Being diagnosed in 15.6% of all children (age<18), AE was the most prevalent chronic-inflammatory condition at all in this age group. The prevalence of AE was 22.8% in one year old children, 8% in adolescents, and 2 to 4% in adults. CONCLUSION: AE is of utmost public health importance in children and adolescents, and also relevant for outpatient healthcare beyond the discipline of dermatology in adults. Despite the higher prevalence in children, approximately 60% of all patients with AE were adults.

SUMO co-expression modifies KV 11.1 channel activity.

AIM: The voltage-gated potassium channel KV 11.1 is the molecular basis for the IKr current, which plays an important role in cardiac physiology. Its malfunction is associated with both inherited and acquired cardiac arrhythmias. Native currents differ from those in experimental models, suggesting additional regulatory mechanisms. We hypothesized that the post-translational modification sumoylation fine-tunes channel activity. METHODS: The functional effects of sumoylation on KV 11.1 were addressed by employing two-electrode voltage-clamp (TEVC) experiments in Xenopus laevis oocytes. Site-directed mutagenesis enabled a further analysis of the SUMO-target amino acids. We assessed protein expression levels and used confocal imaging for localization studies. RESULTS: Co-expression with Ubc9 and SUMO alters the electrophysiological properties of KV 11.1 leading to a decrease in steady-state current amplitude largely due to faster inactivation and alteration of deactivation kinetics. We identified three lysines (K21, K93 and K116) in the PAS domain as the putative SUMO-targets. CONCLUSION: This study indicates KV 11.1 as a sumoylation target and offers three main targets: K21, K93, and K116. Furthermore, it proposes an underlying mechanism for the observed kinetic impact of the PAS domain.

Humpback whale migrations to Antarctic summer foraging grounds through the southwest Pacific Ocean.

Humpback whale (Megaptera novaeangliae) populations typically undertake seasonal migrations, spending winters in low latitude breeding grounds and summers foraging in high latitude feeding grounds. Until recently, a broad scale understanding of whale movement has been derived from whaling records, Discovery marks, photo identification and genetic analyses. However, with advances in satellite tagging technology and concurrent development of analytical methodologies we can now detail finer scale humpback whale movement, infer behavioural context and examine how these animals interact with their physical environment. Here we describe the temporal and spatial characteristics of migration along the east Australian seaboard and into the Southern Ocean by 30 humpback whales satellite tagged over three consecutive austral summers. We characterise the putative Antarctic feeding grounds and identify supplemental foraging within temperate, migratory corridors. We demonstrate that Antarctic foraging habitat is associated with the marginal ice zone, with key predictors of inferred foraging behaviour including distance from the ice edge, ice melt rate and variability in ice concentration two months prior to arrival. We discuss the highly variable ice season within the putative foraging habitat and the implications that this and other environmental factors may have on the continued strong recovery of this humpback whale population.

Parsing disease-relevant protein modifications from epiphenomena: perspective on the structural basis of SOD1-mediated ALS.

Conformational change and modification of proteins are involved in many cellular functions. However, they can also have adverse effects that are implicated in numerous diseases. How structural change promotes disease is generally not well-understood. This perspective illustrates how mass spectrometry (MS), followed by toxicological and epidemiological validation, can discover disease-relevant structural changes and therapeutic strategies. We (with our collaborators) set out to characterize the structural and toxic consequences of disease-associated mutations and post-translational modifications (PTMs) of the cytosolic antioxidant protein Cu/Zn-superoxide dismutase (SOD1). Previous genetic studies discovered >180 different mutations in the SOD1 gene that caused familial (inherited) amyotrophic lateral sclerosis (fALS). Using hydrogen-deuterium exchange with mass spectrometry, we determined that diverse disease-associated SOD1 mutations cause a common structural defect - perturbation of the SOD1 electrostatic loop. X-ray crystallographic studies had demonstrated that this leads to protein aggregation through a specific interaction between the electrostatic loop and an exposed beta-barrel edge strand. Using epidemiology methods, we then determined that decreased SOD1 stability and increased protein aggregation are powerful risk factors for fALS progression, with a combined hazard ratio > 300 (for comparison, a lifetime of smoking is associated with a hazard ratio of ~15 for lung cancer). The resulting structural model of fALS etiology supported the hypothesis that some sporadic ALS (sALS, ~80% of ALS is not associated with a gene defect) could be caused by post-translational protein modification of wild-type SOD1. We developed immunocapture antibodies and high sensitivity top-down MS methods and characterized PTMs of wild-type SOD1 using human tissue samples. Using global hydrogen-deuterium exchange, X-ray crystallography and neurotoxicology, we then characterized toxic and protective subsets of SOD1 PTMs. To cap this perspective, we present proof-of-concept that post-translational modification can cause disease. We show that numerous mutations (N➔D; Q➔E), which result in the same chemical structure as the PTM deamidation, cause multiple diseases. Copyright © 2017 John Wiley & Sons, Ltd.

Polyunsaturated fatty acids are potent openers of human M-channels expressed in Xenopus laevis oocytes.

AIM: Polyunsaturated fatty acids have been reported to reduce neuronal excitability, in part by promoting inactivation of voltage-gated sodium and calcium channels. Effects on neuronal potassium channels are less explored and experimental data ambiguous. The aim of this study was to investigate anti-excitable effects of polyunsaturated fatty acids on the neuronal M-channel, important for setting the resting membrane potential in hippocampal and dorsal root ganglion neurones. METHODS: Effects of fatty acids and fatty acid analogues on mouse dorsal root ganglion neurones and on the human KV 7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. RESULTS: Extracellular application of physiologically relevant concentrations of the polyunsaturated fatty acid docosahexaenoic acid hyperpolarized the resting membrane potential (-2.4 mV by 30 µm) and increased the threshold current to evoke action potentials in dorsal root ganglion neurones. The polyunsaturated fatty acids docosahexaenoic acid, α-linolenic acid and eicosapentaenoic acid facilitated opening of the human M-channel, comprised of the heteromeric human KV 7.2/3 channel expressed in Xenopus oocytes, by shifting the conductance-vs.-voltage curve towards more negative voltages (by -7.4 to -11.3 mV by 70 µm). Uncharged docosahexaenoic acid methyl ester and monounsaturated oleic acid did not facilitate opening of the human KV 7.2/3 channel. CONCLUSIONS: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability.

Does calmitine, a protein specific for the mitochondrial matrix of skeletal muscle, play a key role in mitochondrial function?

The effect of the myotoxic drug chlorpromazine was studied in vitro on proteins of sarcoplasmic reticulum and mitochondrial matrix of skeletal muscle in the normal mouse. Our results indicate that the drug is specific for calcium-binding proteins (calcium ATPase, calsequestrin and calmitine). Its proteolytic effect on these proteins, apparently due to the stimulation of specific proteases, could account for its myotoxic action. Moreover, calsequestrin (sarcoplasmic reticulum) and calmitine (mitochondrial matrix) were not sensitive to the same proteases. Proteases acting on calmitine were inhibited by alpha 2-macroglobulin but not those acting on calsequestrin. Despite some similarities between these two proteins, their characteristics of localization and sensitivity of their proteases indicate that calmitine has a specificity within the mitochondrial matrix and very probably plays a major role in the mitochondrial regulation of free calcium, which controls the activity of various enzymes of the mitochondrial matrix involved in ATP synthesis.

Menopausal women as decision makers in health care.

The findings of a preliminary analysis of data from a study now being conducted to design and evaluate an educational intervention to aid women in becoming more effective decision-makers regarding menopause, self-care strategies, and hormone replacement therapy (HRT), indicate that the lack of attention to the symptoms and health effects of menopause has resulted in frustration and dissatisfaction among women health care consumers. Women in the menopausal years are not informed adequately nor empowered to participate in decision making around issues related to their own health. They do not have the information they want and they do not know where to get it.

The soluble receptor of interleukin 2 is not a serum marker of the autoimmune activity in type I diabetes mellitus.

In order to determine if soluble interleukin 2 receptor (IL2R) was useful as a marker in screening for early Type 1 diabetes and in monitoring immunological treatment, we assayed serum IL2R levels in 67 controls, 43 patients with newly diagnosed diabetes and 28 first degree relatives of diabetic patients (5 subjects were islet cell antibody positive). In 23 diabetes, specimens were analysed at 3 and 6 months after diagnosis whether or not cyclosporin A was administered. Seven patients were in a clinical trial using anti IL2R monoclonal antibody and cyclosporin A. Since IL2R level in the normal population is elevated in the first 5 years of life then decreases until adulthood (age:IL2R correlation between 0 and 15 years: r = -0.42, P less than 0.05), subjects were carefully matched in age. In recent onset diabetes, this negative correlation disappeared and IL2R levels tended to decrease particularly in younger subjects. In Type 1 prediabetic subjects presenting persistent islet-cell antibody serum IL2R was not elevated. During immunological treatment of recent onset diabetes, serum IL2R remained stable and was not modified by cyclosporin A. As expected IL2R became undetectable during treatment with anti IL2R MC Ab. But it rebounded when treatment was stopped with no effect on remission. We concluded that IL2R levels in Type 1 diabetic patients is not useful in screening autoimmune activity or in evaluating the effectiveness of immunosuppressors.

Mdx mouse skeletal muscle: could a mitochondrial factor be responsible for the absence of progressive necrosis?

We compared the myotoxic effect of chlorpromazine on mitochondria of gastrocnemius muscle in X-related muscular dystrophy (mdx) and control mice relative to changes in calmitine and calcium concentrations before and 3 and 6 days after a single injection of the drug. The results indicate that mdx mouse mitochondria are less sensitive to the myotoxic effect of chlorpromazine; calmitine and calcium binding were only slightly reduced compared to controls. Our observations indicate that the calmitine structure could differ in mdx and control mice with respect to calcium binding structures, and that the presence of calmitine in the mitochondria of mdx mouse skeletal muscle could explain why muscle degeneration does not occur in these animals. However, the muscles of patients with Duchenne muscular dystrophy (DMD) are lacking in calmitine and are subject to extensive progressive degeneration.

Calmitine: a calcium-binding mitochondrial protein specific for fast-twitch muscle fibers.

Mitochondrial fractions were isolated from fast-twitch (EDL), slow-twitch (soleus) and heart muscle of normal rat (WKY). Protein separation by electrophoresis and study of calcium-45 binding showed that a specific calcium protein (designated as calmitine) was present in the mitochondria of fast-twitch muscle but practically inexistent in slow-twitch and cardiac muscle. It seems to be related to calcium uptake by an energy-dependent mechanism.

Effect of torbafylline on mitochondrial calmitine in mouse skeletal muscle regeneration after injection of a myotoxic drug.

The effect of torbafylline, a xanthine derivative (Hoechst, Werk Albert, Wiesbaden, Germany), was tested relative to changes in degeneration and subsequent regeneration processes in mouse gastrocnemius muscle induced by a single injection of chlorpromazine, a myotoxic drug. These processes were monitored by measuring changes in calmitine, a mitochondrial protein. We determined in our previous work that calmitine concentration decreases during degeneration and progressively increases during regeneration. In this study, we compared effects in torbafylline-treated mice with those in control mice treated with saline solution. The results show that regeneration is much faster with torbafylline treatment. Calmitine is decreased and returns quickly to normal in torbafylline-treated mice as compared to those treated with saline solution. Torbafylline might thus prove effective in stimulating muscle regeneration in myopathy.

Muscular dystrophy: possible role of mitochondrial deficiency in muscle degeneration processes.

We isolated mitochondria from fast-twitch (extensor digitorum longus) and slow-twitch (soleus) skeletal muscle of the adult rat in normal conditions and 45 days after denervation as well as from skeletal muscle (gastrocnemius) of control and dystrophic (C57BL6J dy/dy and mdx) mice. We searched for the presence of a calcium-specific mitochondrial protein (calmitine) and measured calcium uptake in mitochondria. Our results indicate a possible correlation between the quantity of calmitine present and calcium entry into mitochondria. Both these parameters were elevated in rat fast-twitch and mouse mixed muscle and very low in slow-twitch muscle. They were also very low in dystrophic mouse muscle (C57BL6J dy/dy) with extensive muscle degeneration, but on the contrary elevated in muscle (mdx) with no important signs of degeneration. Finally, we found a normal calmitine concentration and very low calcium uptake in rat extensor digitorum longus after 45 days of denervation. On the basis of these results, it is hypothesized that calmitine synthesis could be subject to neural influence, thus specific for fast-twitch muscle, and that it could be linked to mitochondrial calcium uptake. A decrease in uptake could disturb certain enzymatic activities related to ATP synthesis and bring about muscle degeneration by inhibiting such synthesis. This would occur in the context of reduced calmitine synthesis in the case of genetic anomalies and of inactivation of calmitine after neural disturbance in the case of denervation.