Concomitant Features Research Articles

The Rabbit Corneal Pocket Assay.

The rabbit corneal micropocket angiogenesis assay uses the avascular cornea as a substrate canvas to study angiogenesis in vivo. Through the use of standardized slow-release pellets, a predictable angiogenic response is generated over the course of 1-2 weeks and then quantified. Uniform slow-release pellets are prepared by mixing purified angiogenic growth factors such as basic fibroblast growth factor or vascular endothelial growth factor and a synthetic polymer to allow slow release. A micropocket is surgically created in the rabbit cornea under anesthesia and a pellet implanted. On the days later, the angiogenic response is measured and qualified using a slit lamp, as well as the concomitant vascular phenotype or inflammatory features. The results of the assay are used to assess the ability of potential therapeutic molecules to modulate angiogenesis in vivo, both when released locally or given by ocular formulations or through systemic treatment. In this chapter, the experimental details of the rabbit cornea assay and technical implementations to the original protocol are described.

Surveying the landscape of MDS/MPN research: overlap among the overlap syndromes?

The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) lie at the interphase of phenotypically opposing bone marrow malignancies. They are characterized by concomitant features of bone marrow failure and myeloproliferation and are generally associated with a poor prognosis. Although much is unknown with respect to the clinical course and molecular biology of MDS/MPNs, emerging research is beginning to uncover the key defining characteristics of this designation. In this review, we will discuss the features of MDS/MPN diseases that unify there clinical and molecular course and those that define distinct disease entities. We will discuss advances in genetics and MDS/MPN modeling, as well as translational discoveries that are anticipated to inform the diagnosis, prognostication, and treatment of MDS/MPNs in the near future.

Guidelines for the Standardization of Acute Graft-Versus-Host Disease Clinical Data Collection: An International Consensus Report

Clinical GVHD staging varies between centers and is not agreed upon by independent reviewers (Weisdorf, BBMT 2003). These inconsistencies help explain why promising GVHD treatments from single center studies have not reproduced in multicenter trials. To address this issue, our international GVHD research consortium has developed guidance that has been refined through consensus following case discussions, resulting in uniform and reproducible GVHD clinical symptom reporting.We record all raw target organ symptom data and apply staging based upon this data (Table 1). Only areas of erythema, bullae and desquamation are quantified because other skin changes are not typical of active GVHD rash. Upper GI symptoms must meet thresholds to diagnose GVHD: anorexia with associated weight loss, nausea and/or 2+ vomiting episodes/day lasting 3+ days. For lower GI GVHD we collect stool volumes excluding formed/mostly-formed stools. Unquantified episodes are counted at 200 ml per episode (3 ml/kg for children <50kg) based upon a chart review of 300 patients with post-BMT diarrhea from any cause. Non-GVHD rectal bleeding that results in flecks or streaks of blood in the stool are ignored for staging. We use the highest daily stool output in the 3 days prior to the diagnosis of lower GI GVHD to determine onset stage and, when available, a 3-day average stool volume for subsequent staging to smooth daily variability.We classify biopsy report interpretation into four standardized categories: Positive (unequivocal presence of GVHD), Equivocal (findings suggestive of GVHD, but the pathologist cannot confirm the diagnosis), Non-diagnostic (no abnormalities or subtle findings insufficient to determine etiology), and Non-GVHD etiology (definitive evidence of another diagnosis without concomitant features suggestive of GVHD). We then combine the biopsy interpretation with clinical decision making to assign an overall confidence level to the diagnosis of GVHD in each target organ (Table 2): Confirmed (positive biopsy, regardless of clinician treatment decision), Probable (GVHD diagnosis is sufficiently favored that treatment is given without a positive biopsy), Possible (symptoms present without a positive biopsy; not treated as GVHD), Negative (no symptoms or symptoms are present but a GVHD diagnosis is not entertained and a non-GVHD etiology is identified).Uniform clinical data collection is essential for future GVHD trials and requires application of clear guidance. While still subject to refinement, these guidelines, in use for 2 years by an international research consortium, are designed to be clear, easy to apply, and for clinical trial use.Table 1GVHD Target Organ StagingStageSkin (active erythema only)Liver (bilirubin)Upper GILower GI (stool output/day)0No active (erythematous) GVHD rash< 2 mg/dlNo or intermittent nausea, vomiting or anorexiaAdult: < 500 ml/day or <3 episodes/day Child: < 10 ml/kg/day or <4 episodes/day1Rash < 25% BSA2-3 mg/dlPersistent nausea, vomiting or anorexiaAdult: 500-999 ml/day or 3-4 episodes/day Child: 10 -19.9 ml/kg/day or 4-6 episodes/day2Rash 25 - 50% BSA3.1-6 mg/dl-Adult: 1000-1500 ml/day or 5-7 episodes/day Child: 20 - 30 ml/kg/day or 7-10 episodes/day3Rash > 50% BSA6.1-15 mg/dl-Adult: >1500 ml/day or >7 episodes/day Child: > 30 ml/kg/day or >10 episodes/day4Generalized rash (>50% BSA) and bullous formation or desquamation > 5% BSA>15 mg/dl-Severe abdominal pain with or without ileus, or grossly bloody stool (volume independent)Table 2Confidence LevelsPathologic evidenceClinician assessmentTreatment for acute GVHDCommentsConfirmedUnequivocal evidence of GVHDGVHD is the etiology for symptomsNot requiredGVHD is clearly present even if other etiologies co-exist simultaneouslyProbableNot required (includes equivocal and non-diagnostic biopsies)GVHD most likely etiology for symptomsYesGVHD is most likely present but other etiologies may also explain the symptoms and there insufficient evidence to make a confirmed diagnosisPossibleGVHD in differential diagnosis (but no treatment is being provided)NoGVHD may be present, but other etiologies are favoredNegativeUnequivocal evidence of a diagnosis other than GVHD (e.g., drug rash)GVHD is not considered as an explanation for the symptomsNo and the symptoms resolve without GVHD treatmentA "negative" biopsy (e.g., normal skin) is not unequivocal evidence of a diagnosis other than GVHD DisclosuresDevine:Genzyme: Research Funding. Chen:Bayer: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Consultancy.

Criteria Used in Clinical Practice to Guide Immunosuppressive Treatment in Patients with Primary Sclerosing Cholangitis.

Background & AimsCurrent guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC.MethodsThis is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks.ResultsA simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002).ConclusionsThis is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines.

Giant cell lesions associated with primary hyperparathyroidism

To evaluate the prevalence, clinical features, diagnostic laboratory values and treatment outcome of giant cell lesions (brown tumors) associated with primary hyperparathyroidism (PHPT) in oral and maxillofacial region. A 5 year retrospective data was analyzed wherein all histopathologically proven cases of giant cell lesions involving oral and maxillofacial region were evaluated. Out of these cases, those associated with PHPT were tabulated. Correlation was established with other concomitant clinical features and also with the laboratory values of altered serum calcium, phosphate, alkaline phosphate and parathormone. Follow up of these cases after the correction of PHPT was also noted. Out of 85 cases of histopathologically proven giant cell lesions, five cases were associated with PHPT. There was involvement of maxilla and mandible in one case each. Only frontal bone was involved in two cases. Fifth case had multiple lytic lesions in maxilla and frontal bone. All patients consistently showed very high values of alkaline phosphate and parathormone. Hypercalcemia and hypophosphatemia was noted in four cases. All cases showed regression of the lytic lesion after parathyroidectomy obviating the need for surgical excision of the jaw lesions. Giant cell lesions (brown tumors) associated with PHPT in oral and maxillofacial region are rare clinical entities. The prevalence of PHPT associated giant cell lesions is 5.9 %. They are clinically, radiologically and histopathologically similar to any other peripheral or central giant cell tumor. Relevant history may alert the clinician and altered biochemical values may help in correlating the oral and maxillofacial findings with the underlying systemic disease. At times, the brown tumor maybe the only presenting sign leading to the diagnosis of PHPT.

A commentary on: "A 12-year population-based study of freezing of gait in Parkinson's disease".

A commentary on: "A 12-year population-based study of freezing of gait in Parkinson's disease".

Waldenström macroglobulinemia: What a hematologist needs to know

Waldenström macroglobulinemia (WM) is a distinct hematologic malignancy characterized by a lymphoplasmacytic bone marrow infiltration and the presence of immunoglobulin (Ig)M monoclonal protein. Patients typically present at an advanced age, and a substantial proportion are asymptomatic at diagnosis. A unifying diagnosis of WM may be missed by an unsuspecting hematologist, as symptomatic patients present with a multitude of non-specific manifestations. Although constitutional and neuropathy-related symptoms predominate, concomitant IgM-induced hyperviscosity-associated features can provide useful diagnostic clues. There are specific indications for initiation of therapy. This review focuses on the most up-to-date management strategies of WM, in addition to highlighting the recent discoveries of MYD88 and CXCR4 mutations that have shed unprecedented light on the complex signaling pathways, and opened avenues for novel therapeutic targeting. Although WM remains incurable, with the rapid emergence and integration of effective novel therapies, its clinical course appears poised to improve in the foreseeable future.

Cerebral Perivascular Spaces Visible on Magnetic Resonance Imaging: Development of a Qualitative Rating Scale and its Observer Reliability

Background: Perivascular spaces (PVS) are an important component of cerebral small vessel disease (SVD), several inflammatory disorders, hypertension and blood-brain barrier breakdown, but are difficult to quantify. A recent international collaboration of SVD experts has highlighted the need for a robust, easy-to-use PVS rating scale for the effective investigation of the diagnostic and prognostic significance of PVS. The purpose of the current study was to develop and extend existing PVS scales to provide a more comprehensive scale for the measurement of PVS in the basal ganglia, centrum semiovale and midbrain, and to test its intra- and inter-rater agreement, assessing reasons for discrepancy. Methods: We reviewed previously published PVS scales, including site of PVS assessed, rating method, and size and morphological criteria. Retaining key features, we devised a more comprehensive scale in order to improve the reliability of PVS rating. Two neuroradiologists tested the new scale in MRI brain scans of 60 patients from two studies (stroke, ageing population), chosen to represent a full range of PVS, and demonstrating concomitant features of SVD such as lacunes and white matter hyperintensities. We rated basal ganglia, centrum semiovale, and midbrain PVS. Basal ganglia and centrum semiovale PVS were rated 0 (none), 1 (1-10), 2 (11-20), 3 (21-40) and 4 (>40), and midbrain PVS were rated 0 (none visible) or 1 (visible). We calculated kappa statistics for rating, assessed consistency in use of PVS categories (Bhapkar test) and reviewed sources of discrepancy. Results: Intra- and inter-rater kappa statistics were highest for basal ganglia PVS (range 0.76-0.87 and 0.8-0.9, respectively) than for centrum semiovale PVS (range 0.68-0.75 and 0.61-0.8, respectively) or midbrain PVS (inter-rater range 0.51-0.52). Inter-rater consistency was better for basal ganglia compared to centrum semiovale PVS (Bhapkar statistic 2.49-3.72, compared to 6.79-21.08, respectively). Most inter-rater disagreements were due to very faint PVS, coexisting extensive white matter hyperintensities (WMH) or the presence of lacunes. Conclusions: We developed a more inclusive and robust visual PVS rating scale allowing rating of all grades of PVS severity on structural brain imaging. The revised PVS rating scale has good observer reliability for basal ganglia and centrum semiovale PVS, best for basal ganglia PVS, and moderate reliability for midbrain PVS. Agreement is influenced by PVS severity and the presence of background features of SVD. The current scale can be used in further studies to assess the clinical implications of PVS.

Narrative Exposure Therapy for Treating PTSD With Psychotic Features

Posttraumatic stress disorder (PTSD) with secondary psychotic features is a syndrome that comprises PTSD symptoms followed in time by the additional appearance of psychotic features. Although diagnostic criteria for this condition are not available, the clinical description of this condition has been described especially in individuals who have experienced severe, chronic, multiple traumatic events. This case study presents the treatment of a survivor of torture with severe PTSD and concomitant psychotic features using the psychosocial approach as a theoretical framework of the clinical presentation and narrative exposure therapy (NET) as a psychotherapeutic intervention. NET could be a useful psychotherapeutic tool in relieving symptoms related to severe PTSD with secondary psychotic features. The overall implications involved in working with survivors of torture are also discussed.

Giant Cell Lesions Associated with Primary Hyperparathyroidism.

To evaluate the prevalence, clinical features, diagnostic laboratory values and treatment outcome of giant cell lesions (brown tumors) associated with primary hyperparathyroidism (PHPT) in oral and maxillofacial region. A 5year retrospective data was analyzed wherein all histopathologically proven cases of giant cell lesions involving oral and maxillofacial region were evaluated. Out of these cases, those associated with PHPT were tabulated. Correlation was established with other concomitant clinical features and also with the laboratory values of altered serum calcium, phosphate, alkaline phosphate and parathormone. Follow up of these cases after the correction of PHPT was also noted. Out of 85 cases of histopathologically proven giant cell lesions, five cases were associated with PHPT. There was involvement of maxilla and mandible in one case each. Only frontal bone was involved in two cases. Fifth case had multiple lytic lesions in maxilla and frontal bone. All patients consistently showed very high values of alkaline phosphate and parathormone. Hypercalcemia and hypophosphatemia was noted in four cases. All cases showed regression of the lytic lesion after parathyroidectomy obviating the need for surgical excision of the jaw lesions. Giant cell lesions (brown tumors) associated with PHPT in oral and maxillofacial region are rare clinical entities. The prevalence of PHPT associated giant cell lesions is 5.9%. They are clinically, radiologically and histopathologically similar to any other peripheral or central giant cell tumor. Relevant history may alert the clinician and altered biochemical values may help in correlating the oral and maxillofacial findings with the underlying systemic disease. At times, the brown tumor maybe the only presenting sign leading to the diagnosis of PHPT.

Marine enzymes and food industry: insight on existing and potential interactions

Evidence that support the marine environment as source of useful biocatalysts for application in several areas of industry pile up, both as scientific reports or patent applications. Marine microorganisms have to endure habitats characterized by extreme conditions of salinity, temperature or pressure. Their enzymes present concomitant features, viz. thermostability or halostability, which are appealing for practical applications. The food sector is a field where enzymes are used, given their specificity, compliance with strict regulations, relatively mild operational conditions required and environmental friendly nature. The specific features presented by marine enzymes can be advantageously used both for process improvement or to develop new processes and products. In the present review the role of relevant types of enzymes for the food sector is described and recent findings on those enzymes from marine are put into context. The information provided is illustrative that in spite of the relative novelty concerning the use of marine enzymes within the scope of the food sector, some processes have reached commercial status and promising results are being obtained with several others. Moreover, there is still a vast field of resources for enzyme activity to be explored, namely since the screening process that has been considerably improved with the contribution of metagenomic libraries. It can thus be considered that future and exciting developments can be expected concerning the use of marine enzymes in the food and feed areas.

Retracted: Chronic Recurrent Multifocal Osteomyelitis with Concomitant Features of Juvenile Idiopathic Arthritis

[This retracts the article DOI: 10.1155/2011/210795.].

The link between negative affect, vagal tone, and visceral sensitivity in quiescent Crohn's disease.

Autonomic dysfunction and mood disorders are frequently described in Crohn's disease (CD) and are known to influence visceral sensitivity. We addressed the link between vagal tone, negative affect, and visceral sensitivity in CD patients without concomitant features of irritable bowel syndrome (IBS). Rectal distensions to a discomfort threshold of 70% and onset of pain were performed in nine CD patients in remission and eight healthy controls. Autonomic parameters were evaluated with heart rate variability and electrodermal reactivity. We showed that CD patients had (i) higher scores of depressive symptomatology (12±3 in patients vs 4±1 in controls on the Center for Epidemiologic Studies-Depression Scale; p=0.038), (ii) reduced vagal tone (HF 257±84ms(2) vs 1607±1032ms(2) , p=0.043; LF 455±153ms(2) vs 1629±585ms(2) , p=0.047), (iii) decreased sympathetic reactivity during an aversive stimulus, and (iv) higher tolerance to rectal distension pressures (43±3mmHg vs 30±2mmHg, p=0.002) and low sensitivity index scores. In conclusion, our results provide preliminary evidence that patients with quiescent CD, in the absence of IBS, are hyposensate to experimental rectal distension. These data provide further evidence that anxiety and depressive symptomatology in addition to autonomic dysfunction modulate visceral pain perception in quiescent CD patients in the absence of IBS.

Examining the Relation of Osteochondral Lesions of the Talus to Ligamentous and Lateral Ankle Tendinous Pathologic Features: A Comprehensive MRI Review in an Asymptomatic Lateral Ankle Population

Given the frequency and burden of ankle sprains, the pathologic features identified on magnetic resonance imaging (MRI) scans are widely known in the symptomatic population. Ankle MRI pathologic features in the asymptomatic population, however, are poorly understood. Such examinations are rarely undertaken unless an ankle has been injured or is painful. We report the systematic MRI findings from the reports of 108 consecutive asymptomatic lateral ankles (104 patients). Our purpose was to (1) report the prevalence of osteochondral lesions of the talus (OLTs) and pathologic features of the medial and lateral ligaments, peroneal tendons, and superior peroneal retinaculum (SPR); (2) correlate the presence of OLTs with the pathologic features of the medial and lateral ligaments, peroneal tendons, and SPR; and (3) correlate ligamentous discontinuity with the peroneal pathologic features, OLTs, and SPR pathologic features. A total of 16 OLTs (14.81%) were present (13 medial and 3 lateral). Of the 16 patients with OLTs, 8 (50.00%) had concomitant peroneal pathologic findings. Healthy medial and lateral ligaments were noted in 41 patients (37.96%), and ligamentous discontinuity was grade I in 25 (23.15%), II in 32 (29.63%), III in 5 (4.63%), and grade IV in 5 patients (4.63%). A weak positive correlation was found between attenuation or tears of the superficial deltoid and medial OLTs (phi coefficient = 0.23, p = .0191) and a moderate positive correlation between tears of the posterior talofibular ligament and lateral OLTs (phi coefficient = 0.30, p = .0017). Additionally, a moderate positive correlation between ligamentous discontinuity and tendinopathy of the peroneus brevis was noted [Spearman's coefficient(106) = 0.29, p = .0024]. These findings add to the evidence of concomitant pathologic features in the asymptomatic population. To definitively assess causation and evaluate the clinical evolution of radiologic findings, future, prospective, longitudinal cohort studies are necessary.

P838 DISTURBED ENERGY METABOLISM AND LIPID PROFILE AFTER A 4 WEEK HIGH ORAL FRUCTOSE CHALLENGE: POSSIBLE ROLE OF BILE ACIDS

significance is still debated. Since SCCA-IgM immunocomplexes have been associated with more advanced liver disease and increased risk of HCC development, the purpose of this study was to evaluate the occurrence of this biomarker and its possible relation with the presence of NASH at liver biopsy. Methods: In 91 patients with biopsy proven chronic hepatitis C serum samples were tested for SCCA-IgM by ELISA. Sera of 92 consecutive HCV negative patients with histological NAFLD were included as controls. Results: SCCA-IgM was detected in 33% of HCV patients at the time of liver biopsy, but only in 4% of patients with NAFLD. In chronic hepatitis C this biomarker was found more elevated in patients with concomitant histological features of NASH and at multivariate analysis SCCA-IgM and genotype 3 were independently associated with this histologic feature. Referred to NASH, specificity and sensitivity were 97% and 44% for HCV genotype 3 vs 95% and 26% for SCCA-IgM, while PPV and PNV were 80% and 86% for the former vs 70% and 73% for the latter variable. After antiviral treatment, in HCV patients with SVR, SCCA-IgM values decreased significantly during treatment and remained persistently low after the end of therapy, while remained unchanged in the other patients. Conclusions: SCCA-IgM was detectable in about one third of patients with chronic hepatitis C and its presence was significantly associated with histological NASH, independently of the infecting genotype.

Hobnail Variant of Papillary Thyroid Carcinoma: An Institutional Case Series and Molecular Profile

Papillary thyroid carcinoma (PTC) is increasing in incidence while mortality is unchanged. Identifying patients with higher risk of recurrence and death is essential. Case series identify the hobnail variant of PTC (HVPTC), which is characterized by micropapillary architecture, apocrine features, and loss of cellular polarity. Herein, we describe the clinical course, pathologic features, and mutational profile of patients at our institution with HVPTC. A query into the surgical pathologic database (2009-2012) was performed, and clinicopathologic data were collected on all patients carrying the diagnosis of HVPTC. BRAF(V600E) testing was performed on paraffin-embedded blocks using SNaPshot mutational analysis. Twelve patients with HVPTC were identified, with an average age of 54.1±18.8 years. Seven patients (63.6%) were AJCC Stage III or IV at presentation. Tumors were large (3.7±2.0 cm), some were multifocal (33.3%), and frequently with extrathyroidal extension (58.3%), lymphovascular invasion (41.7%), and lymph node metastasis (75%). Forty percent of the patients had concomitant tall cell features (TCF), and two had small foci of undifferentiated (anaplastic) thyroid carcinoma (ATC). Eighty percent of tumors undergoing mutational analysis had the BRAF(V600E) mutation, and the remaining 20% harbored a RET/PTC1 gene rearrangement. No other known thyroid cancer mutations were identified on SNaPshot analysis. At median follow-up of 26 months, four patients had recurrent or persistent disease, one of whom died from the disease one year after surgery. The hobnail variant of PTC has an aggressive behavior, with a high incidence of infiltrative tumors and metastatic disease. Strikingly, all tumors in our series harbored a PTC-associated genetic abnormality, either a BRAF(V600E) mutation (80%) or a RET/PTC1 rearrangement (20%). This histologic variant warrants further study, and patients with this diagnosis should be observed closely for recurrence.

Phonetic feature extraction for context-sensitive glottal source processing

The effectiveness of glottal source analysis is known to be dependent on the phonetic properties of its concomitant supraglottal features. Phonetic classes like nasals and fricatives are particularly problematic. Their acoustic characteristics, including zeros in the vocal tract spectrum and aperiodic noise, can have a negative effect on glottal inverse filtering, a necessary pre-requisite to glottal source analysis. In this paper, we first describe and evaluate a set of binary feature extractors, for phonetic classes with relevance for glottal source analysis. As voice quality classification is typically achieved using feature data derived by glottal source analysis, we then investigate the effect of removing data from certain detected phonetic regions on the classification accuracy. For the phonetic feature extraction, classification algorithms based on Artificial Neural Networks (ANNs), Gaussian Mixture Models (GMMs) and Support Vector Machines (SVMs) are compared. Experiments demonstrate that the discriminative classifiers (i.e. ANNs and SVMs) in general give better results compared with the generative learning algorithm (i.e. GMMs). This accuracy generally decreases according to the sparseness of the feature (e.g., accuracy is lower for nasals compared to syllabic regions). We find best classification of voice quality when just using glottal source parameter data derived within detected syllabic regions.

Treatment of cocaine addiction with amphetamine, a sleep-suppressant drug: associative learning, sleep patterns and clinical perspectives

Dear Editor Stimulants have shown promise as a treatment for cocaine dependence despite resistance in the field to using controlled substances as therapeutic agents for addictive disorders. Conceptually, the goal of substitution pharmacotherapy is to replace a drug of abuse with rapid onset and brief half-life with an agent that has a more gradual onset of action and long halflife to suppress withdrawal and drug craving, reducing the cycle of compulsive use (Grabowski et al. 2004; Mariani and Levin 2012). Within this context, the recent study by Zimmer and colleagues (2013) demonstrated that D-amphetamine treatment during the persistence of a previously established active cocaine self-administration, but not during passive cocaine infusions, resulted in a significant decrease in cocaine-maintained responding under a PR schedule of reinforcement. The authors discussed these findings in terms of associative processes between the drug effect and the environmental cues, culminating into drug-seeking behavior. This potential hypothesis needs to be viewed in relation to an important aspect of addiction, namely the potentiating effect of environmental cues previously paired with drug effects on the development of drug craving in humans (Carter and Tiffany 1999; Niaura et al. 1988). Because several stimuli can become conditioned to the drug for the abusers, the exposure to conditioned reinforcement may lead to relapse into drug-seeking behavior following a period of abstinence thought to play a crucial role in the addictive cycle. Despite these interesting findings by Zimmer and colleagues (2013), one cannot ignore the use of amphetamine by humans. As an alertness-enhancing and euphorigenic drug, amphetamine is frequently used when irregular work/rest patterns cause excessive sleepiness (Akersted and Ficca 1997; Parsons et al. 2006; Robinson and Becker 1986), characterizing it as a sleep deprivation-related drug. In addition, it has been repeatedly demonstrated that sleep deprivation shares similar neurobiological effects with psychostimulants (Demontis et al. 1990; Fadda et al. 1993; Nunes et al. 1994; Tufik 1981a, b). In this scenario, studies from our group have been conducted in order to investigate the relationship between sleep deprivation and addiction. Of note, we demonstrated that the sleep condition affects amphetamine-induced behavioral changes by specifically modulating its conditioned component. Context-dependent behavioral sensitization to amphetamine is potentiated by sleep deprivation procedures, and a sleep rebound period can attenuate it (Calzavara et al. 2008; Frussa-Filho et al. 2004). In the study under consideration, Zimmer et al. (2013) propose a continuous and passive infusion of amphetamine as a potential treatment to reduce the reinforcing effectiveness of cocaine. Nonetheless, this therapeutic approach would suppress the sleep pattern of addicts. Because it has been extensively demonstrated that sleep disorders, which may impair addiction treatment bymodulating the drug–environment conditioning, are concomitant features in patients with addictive disorders (Canellas and de Lecea 2012; Mahfoud et al. 2009), characterizing a vicious cycle, this prolonged substitution pharmacotherapy could be dangerous in the clinic. Indeed, regarding the authors’ findings, the role of the environment needs to be considered not only in the treatment of the contingent cocaine group but also in that of the noncontingent This letter is in memory of Dr. Roberto Frussa-Filho, who dedicated his entire life to Science, because aman is alivewhile his name is still spoken.

P169 Tiotropium is effective in patients with severe asthma without evidence of chronic obstructive pulmonary disease

RationaleGiven the known effectiveness of tiotropium in chronic obstructive pulmonary disease (COPD) and the significant benefit observed in COPD patients with concomitant features of asthma, it is relevant to investigate...

The value of 1800 MHz and 2100 MHz spectrums in India and implications for auction design

The sequence of events leading up to the upcoming auction of 1800MHz spectrum in India has led to the auctions acquiring an extraordinary significance for the future of the Indian mobile industry. A key feature of the auction design proposed by the regulator TRAI is the benchmarking of the reserve price of 1800MHz to the price of 2100 – 3G spectrum revealed in the 2010 auction. In the context of the low number of LTE devices available and the fragmentation in the 1800MHz band, this paper proposes reducing the duration of spectrum holding to ten years (from the current level of twenty years), and calibrating the reserve price of 1800MHz with its value with GSM deployment. An economic model is used to compute the value of startup and incremental 1800MHz spectrum. The estimated values are shown to differ from the value of 2100MHz spectrum at a pan-India level and also in their distribution across circles. A new set of reserve prices are computed based on the estimation. The estimated values are also shown to be close to the AGR-adjusted price revealed in the 2001 auction. A reserve price based on the 2001 auction is also provided. Concomitant features of the auction are suggested to give coherence to the auction design.